Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

PubMed

Scheer, Carina; Kratz, Christian; Witt, Olaf; Creutzig, Ursula; Reinhardt, Dirk; Klusmann, Jan-Henning

2016-09-01

Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. © 2016 Wiley Periodicals, Inc.

Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies.

PubMed

Antun, Ana G; Gleason, Shannon; Arellano, Martha; Langston, Amelia A; McLemore, Morgan L; Gaddh, Manila; el Rassi, Fuad; Bernal-Mizrachi, Leon; Galipeau, Jacques; Heffner, Leonard T; Winton, Elliott F; Khoury, Hanna J

2013-11-01

Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred. While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia. © 2013 American Cancer Society.

Low blood lead levels impair intellectual and hematological function in children from Cartagena, Caribbean coast of Colombia.

PubMed

Alvarez-Ortega, Neda; Caballero-Gallardo, Karina; Olivero-Verbel, Jesus

2017-12-01

Lead produces numerous biochemical and physiological changes in humans, including hematological disorders, toxic effects on the central nervous system and in the function of several organs. The aim of this study was to determine blood lead levels (BLL) in children from Cartagena, Colombia, associating those with hematological and liver damage markers, the intelligence quotient (IQ), as well as with gene expression of the aminolevulinate dehydratase (ALAD), superoxide dismutase 1 (SOD1), gamma interferon (INF-γ), tumor necrosis factor (TNF) and tumor protein (p53). To achieve this purpose, 118 blood samples were collected from children 5-16 years old, with their respective informed consent from their parents. BLL was measured by atomic absorption; hematological parameters were obtained with automated systems; plasma was utilized to analyze hepatic toxicity markers, alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GT) and alkaline phosphatase (ALP); the Kaufman Brief Intelligence Test (K-BIT) was administered to measure the IQ; and gene expression was quantified from blood RNA. The mean BLL was 1.7±0.3μg/dL. A low proportion of the children (3.4%) had BLL above the CDC recommended limit (5μg/dL). BLL were correlated weakly, but negatively with child age, weight, height, body mass index, platelets wide distribution, mean platelet volume, γ-GT and IQ. There were not significant changes in the expression of evaluated genes. These results support the hypothesis that BLL below 5μg/dL may still be a detrimental factor on children's cognitive abilities, development and hematology, in line with recent concerns that there is no safe level of pediatric lead exposure. Copyright © 2017 Elsevier GmbH. All rights reserved.

Toxic elements and associations with hematology, plasma biochemistry, and protein electrophoresis in nesting loggerhead sea turtles (Caretta caretta) from Casey Key, Florida.

PubMed

Perrault, Justin R; Stacy, Nicole I; Lehner, Andreas F; Poor, Savannah K; Buchweitz, John P; Walsh, Catherine J

2017-12-01

Toxic elements (arsenic, cadmium, lead, mercury, selenium, thallium) are a group of contaminants that are known to elicit developmental, reproductive, general health, and immune system effects in reptiles, even at low concentrations. Reptiles, including marine turtles, are susceptible to accumulation of toxic elements due to their long life span, low metabolic rate, and highly efficient conversion of prey into biomass. The objectives of this study were to (1) document concentrations of arsenic, cadmium, lead, mercury, selenium, and thallium in whole blood and keratin from nesting loggerhead sea turtles (Caretta caretta) from Casey Key, Florida and document correlations thereof and (2) correlate whole blood toxic element concentrations to various hematological and plasma biochemistry analytes. Baselines for various hematological and plasma analytes and toxic elements in whole blood and keratin (i.e., scute) in nesting loggerheads are documented. Various correlations between the toxic elements and hematological and plasma biochemistry analytes were identified; however, the most intriguing were negative correlations between arsenic, cadmium, lead, and selenium with and α- and γ-globulins. Although various extrinsic and intrinsic variables such as dietary and feeding changes in nesting loggerheads need to be considered, this finding may suggest a link to altered humoral immunity. This study documents a suite of health variables of nesting loggerheads in correlation to contaminants and identifies the potential of toxic elements to impact the overall health of nesting turtles, thus presenting important implications for the conservation and management of this species. Copyright © 2017 Elsevier Ltd. All rights reserved.

A phase III study evaluating oral glutamine and transforming growth factor-beta 2 on chemotherapy-induced toxicity in patients with digestive neoplasm.

PubMed

Khemissa, Faïza; Mineur, Laurent; Amsellem, Caroline; Assenat, Eric; Ramdani, Mohamed; Bachmann, Patrick; Janiszewski, Chloé; Cristiani, Isabelle; Collin, Fideline; Courraud, Julie; de Forges, Hélène; Dechelotte, Pierre; Senesse, Pierre

2016-03-01

Patients with gastrointestinal (GI) cancer are exposed to cachexia, which is highly correlated with chemotherapy-induced side effects. Research suggests that specific immunonutrients could prevent such toxicities. The primary objective of this phase III study was to evaluate the efficacy of glutamine and transforming growth factor-β2 (TGF-β2) in the prevention of grade 3-4 non-hematological toxicities induced by chemotherapy in patients with GI cancer. We designed a double-blind, randomized, controlled and multicenter trial stratified according to center, type of chemotherapy, presence of cachexia, and age. Patients were randomized to receive either Clinutren Protect(®) (CP) or a control isocaloric diet (without TGF-β2 or glutamine). Between November 2007 and October 2011, 210 patients were enrolled in the study, of which 201 were included in the intention-to-treat analysis. Grade 3-4 non-hematological toxicities were not significantly different between the CP and control groups when evaluated by univariate and multivariate analyses. Likewise, no difference was observed regarding grade 3-4 hematological toxicities or reasons for treatment interruption. This randomized study does not support the hypothesis that oral glutamine and TGF-β2 supplementation is effective to reduce grade 3 or 4 non-hematological toxicities induced by chemotherapy in patients with GI neoplasm. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Clinical, biochemical, and hematological characteristics, disease prevalence, and prognosis of dogs presenting with neutrophil cytoplasmic toxicity.

PubMed

Aroch, Itamar; Klement, Eyal; Segev, Gilad

2005-01-01

Neutrophil cytoplasmic toxicity is manifested as an abnormality in cell size or the cytoplasmic content upon examination of Romanowsky-stained blood smears, and is traditionally associated with infection and inflammation. The purpose of this retrospective study was to investigate the association of such changes with clinical and clinicopathologic characteristics, diseases, and prognoses in dogs. Dogs with neutrophil toxicity (n = 248) were compared with negative controls (n = 248). Statistical analyses included chi-square tests, independent t-tests, nonparametric Mann-Whitney tests, the chi-square trend test, and survival analysis. Dogs with neutrophil toxicity had a significantly higher prevalence of pale mucous membranes, tachycardia, fever, abdominal organomegaly, icterus, melena, and hematuria. Most mean hematologic variables were significantly different between groups. Dogs with neutrophil toxicity had a significantly (P < .05) higher prevalence of leukocytosis, leukopenia, neutrophilia, neutropenia, anemia, hyponatremia, hypokalemia, hypoproteinemia, hypoalbuminemia, and hypocalcemia. The prevalence of pyometra, parvovirus infection, acute renal failure, peritonitis, immune-mediated hemolytic anemia, disseminated intravascular coagulation, pancreatitis, septicemia, and neoplastic disorders was significantly higher among these dogs. Case fatality, hospitalization length, and treatment cost were significantly (P < .001) higher in dogs with neutrophil toxicity. Neutrophil toxicity severity was significantly (P < .0035) and positively associated with neutropenia, and negatively associated with leukocytosis and neutrophilia. A significant trend (P = .05) toward increasing case fatality with an increase of neutrophil toxicity was observed. In the neutrophil toxicity group, dogs with leukopenia (<5.0 X 10(3)/mm3) had a significantly (P < .0001) higher case fatality compared to dogs with normal or high leukocyte counts. We conclude that evaluation of blood smears for neutrophil cytoplasmic toxicity provides useful clinical information and can serve as a good prognostic predictor.

Acute and Subacute Toxicity of Safranal, a Constituent of Saffron, in Mice and Rats

PubMed Central

Hosseinzadeh, Hossein; Sadeghi Shakib, Saied; Khadem Sameni, Abbas; Taghiabadi, Elahe

2013-01-01

The acute and sub-acute toxicity of safranal were studied in rat and mice within 2 and 21 days after exposure, respectively. For subacute toxicity, changes in weight as well as biochemical, hematological and pathological parameters were studied. The intraperitoneal LD50 values of safranal were 1.48 mL/kg in male mice, 1.88 mL/kg in female mice and 1.50 mL/kg in male rats. Oral LD50 values were 21.42 mL/kg in male mice, 11.42 mL/kg in female mice and 5.53 mL/kg in male rats. For subacute toxicity, safranal was administered orally to male rats once daily for 21 days. In hematological tests, a significant decrease in RBC counts, hematocrit, hemoglobin and platelets were observed. Safranal decreased cholesterol, triglyceride and alkalin phosphatase. Lactate dehydrogenase and serum urea nitrogen were increased by safranal. Histological studies indicated that safranal did not have any toxic effect on the heart, liver and spleen. However, pathological changes were seen in the kidney and lung. According to LD50 values, safranal was low-toxic in acute intraperitoneal route and practically non-toxic in acute oral administration in both mice and rats. In subacute toxicity, safranal changed some hematological and biochemical parameters. PMID:24250576

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

PubMed

Giletti, Andrea; Vital, Marcelo; Lorenzo, Mariana; Cardozo, Patricia; Borelli, Gabriel; Gabus, Raúl; Martínez, Lem; Díaz, Lilian; Assar, Rodrigo; Rodriguez, María Noel; Esperón, Patricia

2017-11-15

Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. Genotype distribution and allele frequency were determined for SLC19A1 G 80 A, MTHFR C 677 T and A 1298 C, TYMS 28bp copy number variation, SLCO1B1 T 521 C, DHFR C -1610 G/T, DHFR C -680 A, DHFR A -317 G and DHFR 19bp indel. Multivariate analysis showed that DHFR -1610 G/T (OR=0.107, p=0.018) and MTHFR 677 T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR -1610 CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours. Copyright © 2017 Elsevier B.V. All rights reserved.

Early discharge after high-dose melphalan and peripheral blood stem cell reinfusion in patients with hematological and non-hematological disease.

PubMed

Anastasia, Antonella; Giglio, Fabio; Mazza, Rita; Sarina, Barbara; Todisco, Elisabetta; Bramanti, Stefania; Castagna, Luca

2009-01-01

The purpose of this study was to analyse our experience of early discharge 2 days after high-dose melphalan (HDM) (Day-1) followed by peripheral blood stem cell re-infusion (Day-0) and re-admission on Day +5 in patients with hematological diseases or solid tumors. From 2000 to November 2005, seven patients received tandem Melphalan 200 mg/m(2) HDM with peripheral blood stem cells transplantation (PBSC-T), 130 a single HDM, for a total of 144 procedures. In 123 of them, patients were discharged on Day +1 for re-admission on Day +5 or earlier in the event of complications. Antibiotic prophylaxis was not used. Patients were hospitalised in positive-pressure reverse isolation room during the neutropenic period. Of the 123 procedures eligible for our mixed inpatient-outpatient management regimen, six (5%) required early re-admission for complications. Full engraftment was achieved in all cases. Median time to neutrophil count >0.5 x 10(9)/microL and >1 x 10(9)/microL were 12 and 14 days, respectively. Median time to platelet recovery (>20 x 10(9)/microL) was 13 days. Severe extra-hematological toxicities occurred in 78 (63%) patients: all had oral mucositis and five had associated diarrhoea. During hospitalisation, 94/123 (76%) experienced febrile neutropenia, 20/94 (21%) had documented infection and 74/94 (79%) were considered fever of unknown origin. Median fever duration was 1 day (range 0-11). Median duration of antibiotic treatment was 6 days (range 3-26). Median time to discharge (from Day 0) was 16 days (range 11-57). There was no mortality by on Day +100. Our experience of early discharge after HDM and PBSC-T with re-admission on Day +5 is safe and feasible with acceptable frequency of hematological and extra-hematological toxicities. The regimen allows reduced hospital stay and hence cost savings.

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies.

PubMed

Wuthrick, Evan J; Kamrava, Mitchell; Curran, Walter J; Werner-Wasik, Maria; Camphausen, Kevin A; Hyslop, Terry; Axelrod, Rita; Andrews, David W; Glass, Jon; Machtay, Mitchell; Dicker, Adam P

2011-12-15

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Copyright © 2011 American Cancer Society.

Toxicity studies of nonylphenol and octylphenol: hormonal, hematological and biochemical effects in Clarias gariepinus.

PubMed

Senthil Kumaran, Satyanarayanan; Kavitha, Chokkalingam; Ramesh, Mathan; Grummt, Tamara

2011-11-01

Among the numerous chemicals discharged into aquatic ecosystems, nonylphenol (NP) and octylphenol (OP) have been shown to have a potent effect on the endocrine system of fish; this issue has been clearly dealt with in several studies. The objective of this study was to assess and compare the general toxicity of these estrogenic chemicals individually on Clarias gariepinus. Fish were exposed to different concentrations of both NP and OP (250, 500, 750 and 1000 μg l(-1) ) under semi-static conditions for a period of 7 days. The adverse effect was evaluated with use of blood cell counting, hemoglobin (Hb), hematocrit (HCT), hematimetric indices, bilirubin, protein, glucose, serum transaminases, serum phosphatases, lactate dehydrogenase and cortisol. The results showed a clear indication of anemia, increases in leukocyte count and bilirubin content and a reduction in plasma protein levels with higher concentrations of both the toxicants compared with controls. Furthermore, with all the concentrations the inevitable increase in serum cortisol and plasma glucose showed primary and secondary stress responses. Moreover, probable tissue damage gave rise to a series of fluctuations of enzyme levels at lower concentrations, but a decrease with higher concentrations showed the severity of the effect. Depending on the parameters examined, OP had a relatively greater effect than NP. Overall, these two chemicals seemingly affected hematology and the activity of some enzymes, leading to serious impairment of the metabolism and physiology of C. gariepinus. 2011 John Wiley & Sons, Ltd.

Hematological Toxicity After Robotic Stereotactic Body Radiosurgery for Treatment of Metastatic Gynecologic Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org; Debernardo, Robert; Radivoyevitch, Tomas

Purpose: To evaluate hematological toxicity after robotic stereotactic body radiosurgery (SBRT) for treatment of women with metastatic abdominopelvic gynecologic malignancies. Methods and Materials: A total of 61 women with stage IV gynecologic malignancies treated with abdominopelvic SBRT were analyzed after ablative radiation (2400 cGy/3 divided consecutive daily doses) delivered by a robotic-armed Cyberknife SBRT system. Abdominopelvic bone marrow was identified using computed tomography-guided contouring. Fatigue and hematologic toxicities were graded by retrospective assignment of common toxicity criteria for adverse events (version 4.0). Bone marrow volume receiving 1000 cGy (V10) was tested for association with post-therapy (median 32 days [25%-75% quartile,more » 28-45 days]) white- or red-cell counts, hemoglobin levels, and platelet counts as marrow toxicity surrogates. Results: In all, 61 women undergoing abdominopelvic SBRT had a median bone marrow V10 of 2% (25%-75% quartile: 0%-8%). Fifty-seven (93%) of 61 women had received at least 1 pre-SBRT marrow-taxing chemotherapy regimen for metastatic disease. Bone marrow V10 did not associate with hematological adverse events. In all, 15 grade 2 (25%) and 2 grade 3 (3%) fatigue symptoms were self-reported among the 61 women within the first 10 days post-therapy, with fatigue resolved spontaneously in all 17 women by 30 days post-therapy. Neutropenia was not observed. Three (5%) women had a grade 1 drop in hemoglobin level to <10.0 g/dL. Single grade 1, 2, and 3 thrombocytopenias were documented in 3 women. Conclusions: Abdominopelvic SBRT provided ablative radiation dose to cancer targets without increased bone marrow toxicity. Abdominopelvic SBRT for metastatic gynecologic malignancies warrants further study.« less

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PubMed

Connolly, K J; Allan, J D; Fitch, H; Jackson-Pope, L; McLaren, C; Canetta, R; Groopman, J E

1991-11-01

To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.

Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos

PubMed Central

Mohammod Mostakim, Golam; Zahangir, Md. Mahiuddin; Monir Mishu, Mahbuba; Rahman, Md. Khalilur; Islam, M. Sadiqul

2015-01-01

Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb, Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p < 0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations. PMID:26635877

Mortality and hematology associated with the ingestion of one number four lead shot in black ducks, Anas rubripes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pain, D.J.; Rattner, B.A.

The black duck (anas rubripes) is a dabbling duck endemic to North America. Since population surveys of this species began in the early 1950's, numbers have declined steadily at the rate of approximately 1.5% a year. In 1980 the North American population was estimated to be only 42% of that recorded in 1952. Several reasons have been suggested for this decline. One environmental contaminant that may be contributing to the decline is spent lead gunshot. The ingestion of gunshot by waterfowl is well documented and is thought to kill an estimated 1.6-3.8 million waterfowl each year in North America. Theremore » has been little research concerning the toxicity of lead gunshot to the black duck and the present significance of lead poisoning as a mortality factor in this species. This study reports the results of an experiment in which captive black ducks were dosed with one number four lead shot. Mortality rates and hematological effects are discussed in relation to lead toxicity.« less

Weekly infusional high-dose 5-fluorouracil and leucovorin and biweekly cisplatin: a convenient treatment option in advanced gastric cancer.

PubMed

Kundel, Yulia; Purim, Ofer; Figer, Arie; Stemmer, Salomon M; Tichler, Thomas; Sulkes, Jaqueline; Sulkes, Aaron; Brenner, Baruch

2008-04-01

To summarize our experience using a regimen of weekly 5-FU and leucovorin (LV) and biweekly cisplatin (CDDP) in advanced gastric cancer (AGC). Patients had previously untreated histologically confirmed AGC. Treatment consisted of intravenous weekly infusional 5-FU and LV and biweekly CDDP, given for 6 weeks followed by a 2-week rest. Initially, a lower dose level was used (5-FU 2000 mg/m(2), LV 500 mg/m(2), CDDP 40 mg/m(2)), which was later increased (5-FU 2600 mg/m(2), LV 500 mg/m(2), CDDP 50 mg/m(2)). Forty-five patients were treated, 18 at the lower dose level and 27 at the higher dose level. The median age was 67 years and 55% were male. Grade > or =3 toxicity was documented in 37% of patients but toxicity related hospitalizations or treatment discontinuation occurred in only 22% and 13%, respectively. There were no toxic deaths. The most common hematological toxicities were anemia and neutropenia and the most common non-hematological toxicities were nausea, vomiting and fatigue. Of the 39 patients evaluable for response, 13 (33%) had partial response (PR) and 11 (28%) had stable disease (SD). Control of disease (PR+SD) was achieved in 61%. The higher dose level was associated with a higher response rate (p=0.07) and an increased toxicity (p=0.01), mostly hematological and gastrointestinal. Median progression-free survival and overall survival were 3.5 and 9.2 months, respectively. This regimen appears safe, with a manageable toxicity profile. Efficacy data resemble those reported for more complex and toxic regimens. The higher dose level had enhanced activity, at the expense of increased toxicity.

Four Week Oral Toxicity Study of WR242511 in Dogs. Volume 2

DTIC Science & Technology

1994-06-03

10^6/cmm Erythrocytes 0.00 NO 6.00 6.00 8.00 8.00 2. HGB g/dL Hemoglobin 0.0 NO 12.0 12.0 19.0 19.0 3. HCT % Hematocrit 0.0 NO 35.0 35.0...IS/ UU CAJ U INDIVIDUAL ANIMAL HEMATOLOGY REPORT BY GROUP TEST : Erythrocytes STUDY ID: 134 SEX: MALE STUDY NO: 134 • ABBR...FOUR WEEK ORAL TOXICITY STUDY OF WR242511 IN DOGS DRAFT INDIVIDUAL ANIMAL HEMATOLOGY REPORT BY GROUP TEST: Erythrocytes STUDY ID: 134 STUDY NO

Drug-Induced Hematologic Syndromes

PubMed Central

Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren

2009-01-01

Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. PMID:19960059

Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: Report of RTOG trial 89-05

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phillips, T.L.; Scott, C.B.; Leibel, S.A.

1995-09-30

The purpose of this trial was to determine if the addition of bromodeoxyuridine (BrdUrd) to radiotherapy prolongs survival when compared to radiotherapy alone in patients with brain metastases. Seventy-two patients with brain metastases were randomized to 37.5 Gy in 15 fractions of 2.5 Gy or to the same dose with BrdUrd 0.8 g/m{sup 2} per day for 4 days of each of 3 weeks. Patients were stratified by primary site (breast, lung or other), number of metastases (single or multiple) and age (<60 vs. >60). There was no significant difference between the two treatment arms (p = 0.904). The studymore » was open from October 1989 to March 1993 and accrued 72 patients. Only one patient in the RT only arm remains alive. The two treatment arms were balanced with respect to all stratification variables. Toxicity due to radiotherapy was similar in both arms. BrdUrd caused significant Grade 4 and 5 hematologic and skin toxicity in five patients. Two patients died due to hematologic toxicity and one from a Stevens-Johnson type skin reaction. Phenytoin played a role in the skin reactions and ranitidine was associated with the hematologic deaths. Ranitidine was eliminated, BrdUrd was discontinued after any hematologic toxicity, and no further Grade 4 or 5 toxicities were seen. The median survival was 6.12 months in the radiotherapy group and 4.3 in the BrdUrd group (p = 0.904). Patients with solitary brain metastases had significantly better survival (p = 0.031). BrdUrd did not enhance the efficacy of the radiotherapy regiment tested, in spite of the fact that brain metastases have shown high labeling indices. The toxicity of this schedule of BrdUrd administration was apparently increased by ranitidine and phenytoin. 16 refs., 4 figs., 13 tabs.« less

Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats.

PubMed

Zhang, Xiaofang; Zhang, Xiaodong; Yuan, Bojun; Ren, Lijun; Zhang, Tianbao; Lu, Guocai

2016-11-30

Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0-80 and 0-120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006's NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.

Silibinin: an old drug for hematological disorders.

PubMed

Zou, Hai; Zhu, Xing-Xing; Zhang, Guo-Bing; Ma, Yuan; Wu, Yi; Huang, Dong-Sheng

2017-10-24

Silibinin (silybin), a non-toxic natural polyphenolic flavonoid, is the principal and the most biologically active component of silymarin. It is efficient in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol, hepatitis, and gall bladder disorders. Further, in our previous studies, we explored the anti-cancer efficacy in common cancers, such as lung, prostatic, colon, breast, bladder, as well as, hepatocellular carcinoma. Interestingly, silibinin is still not solely limited to the treatment of these diseases. Recent research endeavors suggest that silibinin may function diversely and serve as a novel therapy for hematological disorders. It discovered several interesting viewpoints in the widely studied mechanisms of silibinin in the hematological disorders. In this report, we review the up-to-date findings of more potency roles of silibinin in β-thalassemia (β-TM), acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL) and multiple myelomas (MM) therapy and attempt to clarify the mechanisms underlying its effects. There are two viewpoints: First, The functional mechanisms of silibinin in AML cells via regulating cell differentiation to exert anti-cancer effect; Second, combination treatment strategy may be a good choice.

Emerging antibody-drug conjugates for treating lymphoid malignancies.

PubMed

Wolska-Washer, Anna; Robak, Pawel; Smolewski, Piotr; Robak, Tadeusz

2017-09-01

Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.

Delayed hematologic toxicity following rattlesnake envenomation unresponsive to crotalidae polyvalent antivenom.

PubMed

Bailey, Abby M; Justice, Stephanie; Davis, George A; Weant, Kyle

2017-07-01

North American rattlesnake envenomations are known to produce coagulopathies and thrombocytopenia. However, the occurrence of delayed hematologic toxicity (less than seven days after envenomation) is poorly characterized in the medical literature. While the recurrence of hematologic derangements has been documented following envenomation, it is usually in the absence of clinically significant bleeding. Although commonly recommended to treat delayed coagulopathies, the effectiveness of crotalidae polyvalent immune Fab ovine (CroFab®) in managing this condition remains in question and warrants further investigation and exploration. We describe the case of a 19-year-old male who presented following rattlesnake envenomation at a church service who was treated with antivenin for 48 h and discharged home only to return four days later with profound thrombocytopenia, coagulopathy, and clinically significant bleeding. Copyright © 2017 Elsevier Inc. All rights reserved.

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer.

PubMed

Šišić, Ibrahim; Pojskić, Belma; Mekić Abazović, Alma; Kovčin, Vladimir

2015-08-01

To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus), leucovorin (folfox) between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC). A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

Effects of Chinese Medicine as Adjunct Medication for Adjuvant Chemotherapy Treatments of Non-Small Cell Lung Cancer Patients

PubMed Central

Jiao, Lijing; Dong, Changsheng; Liu, Jiaxiang; Chen, Zhiwei; Zhang, Lei; Xu, Jianfang; Shen, Xiaoyong; Che, Jiaming; Yang, Yi; Huang, Hai; Li, Hegen; Sun, Jianli; Jiang, Yi; Mao, Zhujun; Chen, Peiqi; Gong, Yabin; Jin, Xiaolin; Xu, Ling

2017-01-01

The aim was to evaluate the effects of traditional Chinese medicine (TCM) as a combination medication with adjuvant chemotherapy on postoperative early stage non-small cell lung cancer (NSCLC) patients. The 314 patients with completely resected stage IB, II or IIIA cancers were assigned into vinorelbine plus cisplatin/carboplatin (NP/NC) (control, n = 158) and NP/NC with additional TCM (intervention, n = 156) groups. The primary endpoint was QOL scores; secondary endpoints were the toxicity and safety of the regimens. The NP/NC regimen caused mild (grade 1 or 2) non-hematologic toxic effects in the patients comprising vomiting (43.6%), fatigue (36.9%), pain (23%), dry mouth (27.6%) and diarrhea (7.9%). The incidence of adverse events was significantly lower in the intervention group than in the control group (0.57% vs 4.02%, P = 0.037). Transient severe (grade 3 or 4) hematological toxic effects occurred less often (hemoglobin reduction (11.9 vs 22.5 percent) and total bilirubin increased (to 42.1 vs 46.2%) in the intervention compared to the control group during the 2nd chemotherapy cycle. When combined with adjuvant chemotherapy, TCM led to partial relief of symptoms in addition to a reduction of side-effects and adverse events caused by the NP/NC regimens. PMID:28436479

Methotrexate: the emerging drug of choice for serious rheumatoid arthritis.

PubMed

Salach, R H; Cash, J M

1994-01-01

The recently recognized high morbidity and unexpected mortality associated with rheumatoid arthritis (RA) has spurred new interest in more aggressive, early treatment of this disease. Methotrexate (MTX) has rapidly become the rheumatologist's drug of choice for serious RA because of its favorable efficacy to toxicity ratio and rapid onset of action compared with other second-line agents. The initial concerns about hepatic fibrosis and cirrhosis in psoriatic patients has subsided somewhat as long-term liver toxicity data are accumulating in patients with RA. Routine liver biopsy with incremental doses of MTX is no longer recommended. Potential for severe lung, hematologic, and infectious complications exists, mandating careful monitoring of RA patients taking MTX.

Acute toxicity study of cisplatin loaded long-circulating and pH-sensitive liposomes administered in mice.

PubMed

Leite, Elaine A; Lana, Angela M Q; Junior, Alvaro D Carvalho; Coelho, Luiz G V; De Oliveira, Mônica C

2012-04-01

Cisplatin (CDDP) is a very active and cytotoxic agent but causes severe side effects, namely nephrotoxicity, which limits the therapy. The present study aimed to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), as compared to free CDDP, after their intravenous administration in mice. After the administration of free CDDP or SpHL-CDDP at different doses, the body weight was recorded and the LD50 and the maximum tolerated dose (MTD) were calculated. Blood samples were collected for hematological and biochemical analysis. Kidneys, liver, spleen, and bone marrow were removed for histopathological examination. A reduction of body weight of less than 15% could be observed in male and female mice after treatment with free CDDP and SpHL-CDDP at doses of < or = 10 mg/kg and 20 mg/kg, respectively. The LD50 and MTD values obtained after SpHL-CDDP administration were approximately two and three times higher, respectively, than those obtained using free CDDP. Changes in hematological parameters and hematopoietic tissue morphology showed the appearance of toxicity induced by free CDDP. By contrast, the absence of mielotoxicity after SpHL-CDDP treatment could be observed. As regards nephrotoxicity, no alteration in blood urea and creatinine levels, nor morphological change in kidneys, could be observed in mice treated with SpHL-CDDP, as compared to saline-treatment control group. The results showed that SpHL-CDDP at its MTD (20 mg/kg), as compared to the administration of free CDDP at its MTD (7.5 mg/kg), significantly reduced the renal toxicity. Thus, SpHL-CDDP can eliminate CDDP-induced toxicity and is a promising candidate for the intravenous therapy of solid tumors.

Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

PubMed

Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

2016-08-01

Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

Protective mechanism of turmeric (Curcuma longa) on carbofuran-induced hematological and hepatic toxicities in a rat model.

PubMed

Hossen, Md Sakib; Tanvir, E M; Prince, Maruf Billah; Paul, Sudip; Saha, Moumoni; Ali, Md Yousuf; Gan, Siew Hua; Khalil, Md Ibrahim; Karim, Nurul

2017-12-01

Turmeric (Curcuma longa L. [Zingiberaceae]) is used in the treatment of a variety of conditions including pesticide-induced toxicity. The study reports the antioxidant properties and the protective effects of turmeric against carbofuran (CF)-induced toxicity in rats. The antioxidant potential was determined by using free radicals scavenging activity and ferric reducing antioxidant power values. Male Wistar rats were randomly divided into four groups, designated as control, turmeric (100 mg/kg/day), CF (1 mg/kg/day) and turmeric (100 mg/kg/day) + CF (1 mg/kg/day) treatments. All of the doses were administered orally for 28 consecutive days. The biological activity of the turmeric and CF was determined by using several standard biochemical methods. Turmeric contains high concentrations of polyphenols (8.97 ± 0.15 g GAEs), flavonoids (5.46 ± 0.29 g CEs), ascorbic acid (0.06 ± 0.00 mg AEs) and FRAP value (1972.66 ± 104.78 μM Fe 2+ ) per 100 g of sample. Oral administration of CF caused significant changes in some of the blood indices, such as, mean corpuscular volume, corpuscular hemoglobin, white blood cell, platelet distribution width and induced severe hepatic injuries associated with oxidative stress, as observed by the significantly higher lipid peroxidation (LPO) levels when compared to control, while the activities of cellular antioxidant enzymes (including superoxide dismutase and glutathione peroxidase) were significantly suppressed in the liver tissue. Turmeric supplementation could protect against CF-induced hematological perturbations and hepatic injuries in rats, plausibly by the up-regulation of antioxidant enzymes and inhibition of LPO to confer the protective effect.

In Vivo Toxicity Studies of Europium Hydroxide Nanorods in Mice

PubMed Central

Patra, Chitta Ranjan; Abdel Moneim, Soha S.; Wang, Enfeng; Dutta, Shamit; Patra, Sujata; Eshed, Michal; Mukherjee, Priyabrata; Gedanken, Aharon; Shah, Vijay H; Mukhopadhyay, Debabrata

2009-01-01

Lanthanide nanoparticles and nanorods have been widely used for diagnostic and therapeutic applications in biomedical nanotechnology due to their fluorescence properties and pro-angiogenic to endothelial cells, respectively. Recently, we have demonstrated that europium (III) hydroxide [EuIII(OH)3] nanorods, synthesized by the microwave technique and characterized by several physico-chemical techniques, can be used as pro-angiogenic agents which introduce future therapeutic treatment strategies for severe ischemic heart/limb disease, and peripheral ischemic disease. The toxicity of these inorganic nanorods to endothelial cells was supported by several in vitro assays. To determine the in vivo toxicity, these nanorods were administered to mice through intraperitoneal injection (IP) everyday over a period of seven days in a dose dependent (1.25 to 125 mgKg−1day−1) and time dependent manner (8–60 days). Bio-distribution of europium elements in different organs was analyzed by inductively coupled plasma mass spectrometry (ICPMS). Short-term (S-T) and long-term (L-T) toxicity studies (mice sacrificed on day 8 and 60 for S-T and L-T, respectively) show normal blood hematology and serum clinical chemistry with the exception of a slight elevation of liver enzymes. Histological examination of nanorod treated vital organs (liver, kidney, spleen and lungs) showed no or only mild histological changes that indicate mild toxicity at the higher dose of nanorods. PMID:19616569

Safety Assessment of Ocimum Basilicum Hydroalcoholic Extract in Wistar Rats: Acute and Subchronic Toxicity Studies

PubMed Central

Rasekh, Hamid Reza; Hosseinzadeh, Leila; Mehri, Soghra; Kamli-Nejad, Mohammad; Aslani, Majid; Tanbakoosazan, Farahnaz

2012-01-01

Objective(s) Ocimum basilicum L. is widely used in folk medicine of many countries including . Both O. basilicum and its oil extract have received considerable attention for their potential medicinal properties, but there are a few reports about possible toxicity of this plant. Therefore, in the present study, acute and subchronic toxicity of O. basilicum hydroalcohlic extract have been evaluated in Wistar rats. Materials and Methods For the acute toxicity assessment, five groups of 10 animals (5 male, 5 female) received four different single dose of extract orally, the animals were, then, kept under observation for 14 days. For subchronic toxicity, the animals were divided into four groups (5 male, 5 female) and were gavaged daily by 50, 200 and 500 mg/kg of extract. Mortality, clinical signs, body weight changes, food and water consumption, and hematological and biochemical parameters were monitored during the study period. On the 45th day, animals were sacrificed and gross findings, weight of liver and left kidney and liver histological markers were assessed. Results The results of acute study indicated that LD50 of O. basilicum is higher than 5 mg/kg. In subchronic study, no adverse effects were observed on serum parameters in male and female rats. The hematological results showed a reduction in the hematocrit, platelets and RBC in both sexes. No abnormalities were observed in other parameters. Conclusion Based on the results of this study, present data suggest that hematologic system could serve as a target organ in oral toxicity of this plant. PMID:23493182

The Many Faces of Lupus

PubMed Central

El-Gabalawy, Hani

1990-01-01

Systemic lupus erythematosus is a multisystem disorder that presents itself in several different ways. Arthritis, dermatitis, nephritis, and pleuropericarditis are the most common features initially. Various hematologic and neuropsychiatric manifestations are also seen during the course of the disease. Anti-nuclear antibodies are the hallmark of lupus but are nonspecific and detectable in many other disorders. Once the diagnosis is established, the severity of the disease needs to be determined, in particular the extent of major organ involvement. The level of disease activity should be repeatedly estimated using clinical and laboratory parameters. Therapeutic decisions are based on disease severity and activity. Aggressive suppression of major organ inflammation and reduction of long-term toxicity are the main goals of therapy. PMID:21233973

Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients Treated With Intensity-Modulated Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazan, Jose G.; Luxton, Gary; Mok, Edward C.

2012-11-01

Purpose: To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT). Methods and Materials: We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade {>=}3 HT (HT3+) and hematologic event (HE), defined as any grade {>=}2 HT with a modification in chemotherapy dose. Normal tissue complication probabilitymore » (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters. Results: Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD{sub 50} = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose {>=}30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors. Conclusions: LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively.« less

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study.

PubMed

Lombardi, Giuseppe; Rumiato, Enrica; Bertorelle, Roberta; Saggioro, Daniela; Farina, Patrizia; Della Puppa, Alessandro; Zustovich, Fable; Berti, Franco; Sacchetto, Valeria; Marcato, Raffaella; Amadori, Alberto; Zagonel, Vittorina

2015-10-01

Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of ≤3,00,000/mm, methylated O-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

Gastrointestinal surgical emergencies in patients treated for hemathological malignancies.

PubMed

Caronna, R; Cardi, M; Arcese, W; Iori, A P; Martelli, M; Catinelli, S; Mangioni, S; Corelli, S; Priore, F; Tarantino, E; Frantellizzi, V; Spera, G; Borrini, F; Chirletti, P

2005-01-01

Upper and lower gastrointestinal symptoms are major and serious complications in patients who undergo chemotherapy for hematological malignancies. Their most frequent causes are acute intestinal graft-versus-host disease (GVHD) after bone marrow transplant, infections, toxicity or preexisting gastrointestinal diseases. Mortality can reach 30-60% of cases. We report 15 cases operated on for abdominal emergencies: 3 severe gastrointestinal bleeding and 12 acute abdomen. We performed 10 bowel resections, one cholecystectomy, one splenectomy, two laparotomy with pancreatic debridement and peritoneal lavage, and one suture of perforated peptic ulcer. Operative mortality was 33.3% (5/15). Deaths have been reported only in the group of patients with acute abdomen. In all cases death was correlated to generalized sepsis related to immunosuppression. We believe that an aggressive approach, consisting of close monitoring and early laparotomy combined with vigorous supportive therapy, should be used when dealing with suspected gastrointestinal complications in patients with hematological malignancies.

Intravenous apoptotic cell infusion as a cell-based therapy toward improving hematopoietic cell transplantation outcome.

PubMed

Saas, Philippe; Gaugler, Béatrice; Perruche, Sylvain

2010-10-01

Allogeneic hematopoietic cell transplantation (AHCT) is an efficient therapy for different malignant and nonmalignant hematological diseases. However, the use of this therapeutic approach is still limited by some severe toxic side effects, mainly graft-versus-host disease (GvHD). Today, the risk of fatal GvHD restrains the wider application of AHCT to many patients in need of an effective therapy for their high-risk hematologic malignancies. Thus, new strategies, including cell-based therapy approaches, are required. We propose to use intravenous donor apoptotic leukocyte infusion to improve AHCT outcome. In experimental AHCT models, we demonstrated that intravenous apoptotic leukocyte infusion, simultaneously with allogeneic bone marrow grafts, favors hematopoietic engraftment, prevents allo-immunization, and delays acute GvHD onset. Here, we review the different mechanisms and the potential beneficial effects associated with the immunomodulatory properties of apoptotic cells in the AHCT setting. © 2010 New York Academy of Sciences.

Low-dose fotemustine as second-line chemotherapy for recurrent glioblastoma multiforme.

PubMed

De Felice, Francesca; Bulzonetti, Nadia; Musio, Daniela; D'Elia, Alessandro; Salvati, Maurizio; Tombolini, Vincenzo

2013-09-01

To test if fotemustine administrated at low doses during the maintenance phase of gioblastoma therapy could improve the toxicity profile, without reducing progression-free survival at six months (PFS-6). Patients enrolled were affected by recurrent glioblastoma multiforme, proven by magnetic resonance imaging (MRI), at least six months after radiochemotherapy completion. Fotemustine was administered at an induction dose of 100 mg/m(2) followed by a maintenance dose of 75 mg/m(2). All 15 patients completed the induction phase. Eight patients began maintenance-phase therapy and received a median of three cycles (range=2-6). Grade 3 or more haematological toxicity was not documented. The PFS-6 was 5/15 and the median overall survival was 7.5 months. Haematological toxicity compares favourably with trials using the conventional scheme: no grade 3-4 adverse effects were recorded. This low-dose approach could be considered a compromise treatment whilst waiting for definitive standardization of second-line therapy, in order to reduce severe hematological toxicity.

Silibinin: an old drug for hematological disorders

PubMed Central

Zou, Hai; Zhu, Xing-Xing; Zhang, Guo-Bing; Ma, Yuan; Wu, Yi; Huang, Dong-Sheng

2017-01-01

Introduction Silibinin (silybin), a non-toxic natural polyphenolic flavonoid, is the principal and the most biologically active component of silymarin. It is efficient in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol, hepatitis, and gall bladder disorders. Further, in our previous studies, we explored the anti-cancer efficacy in common cancers, such as lung, prostatic, colon, breast, bladder, as well as, hepatocellular carcinoma. Interestingly, silibinin is still not solely limited to the treatment of these diseases. Recent research endeavors suggest that silibinin may function diversely and serve as a novel therapy for hematological disorders. Areas covered It discovered several interesting viewpoints in the widely studied mechanisms of silibinin in the hematological disorders. Expert commentary In this report, we review the up-to-date findings of more potency roles of silibinin in β-thalassemia (β-TM), acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL) and multiple myelomas (MM) therapy and attempt to clarify the mechanisms underlying its effects. There are two viewpoints: First, The functional mechanisms of silibinin in AML cells via regulating cell differentiation to exert anti-cancer effect; Second, combination treatment strategy may be a good choice. PMID:29179521

A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors.

PubMed

Dy, Grace K; Suri, Ajit; Reid, Joel M; Sloan, Jeff A; Pitot, Henry C; Alberts, Steven R; Goldberg, Richard M; Atherton, Pamela J; Hanson, Lorelei J; Burch, Patrick A; Rubin, Joseph; Erlichman, Charles; Adjei, Alex A

2005-06-01

We have previously demonstrated that pemetrexed is clinically active when administered 90 min after gemcitabine in a phase I study. The present study was undertaken to evaluate the efficacy, toxicity, and pharmacokinetics of gemcitabine and pemetrexed when pemetrexed is administered immediately after gemcitabine. A total of 14 patients received 84 cycles of treatment. Gemcitabine 1250 mg/m(2) was administered on days 1 and 8 of each 21-day cycle, and pemetrexed 500 mg/m(2) on day 8 immediately following gemcitabine administration. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for all treatment cycles. Pharmacokinetic analyses of plasma gemcitabine and pemetrexed concentrations were performed. Neutropenia was the most common severe toxicity. Non-hematologic toxicities, which included nausea, vomiting, fatigue, diarrhea, rash, and elevated transaminases were of mild-to-moderate severity. No increased toxicity was observed with this schedule in comparison to the previous phase I schedule. There was no pharmacokinetic interaction between the two drugs. One partial response was documented in a patient with non-small-cell lung cancer. Eight patients had disease stabilization for five or more cycles. Gemcitabine immediately followed by pemetrexed is well tolerated and clinically active, and deserves further evaluation in phase II trials.

Thoracic Vertebral Body Irradiation Contributes to Acute Hematologic Toxicity During Chemoradiation Therapy for Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deek, Matthew P.; Benenati, Brian; Kim, Sinae

Purpose: To determine the relationships between radiation doses to the thoracic bone marrow and declines in blood cell counts in non-small cell lung cancer (NSCLC) patients treated with chemoradiation therapy (CRT). Methods and Materials: We included 52 patients with NSCLC treated with definitive concurrent carboplatin–paclitaxel and RT. Dose-volume histogram (DVH) parameters for the thoracic vertebrae (TV), sternum, scapulae, clavicles, and ribs were assessed for associations with changes in blood counts during the course of CRT. Linear and logistic regression analyses were performed to identify associations between hematologic nadirs and DVH parameters. A DVH parameter of Vx was the percentage ofmore » the total organ volume exceeding x radiation dose. Results: Grade ≥3 hematologic toxicity including neutropenia developed in 21% (n=11), leukopenia in 42% (n=22), anemia in 6% (n=3), and throbocytopenia in 2% (n=1) of patients. Greater RT dose to the TV was associated with higher risk of grade ≥3 leukopenia across multiple DVH parameters, including TV V{sub 20} (TVV) (odds ratio [OR] 1.06; P=.025), TVV{sub 30} (OR 1.07; P=.013), and mean vertebral dose (MVD) (OR 1.13; P=.026). On multiple regression analysis, TVV{sub 30} (β = −0.004; P=.018) and TVV{sub 20} (β = −0.003; P=.048) were associated with white blood cell nadir. Additional bone marrow sites (scapulae, clavicles, and ribs) did not affect hematologic toxicity. A 20% chance of grade ≥3 leukopenia was associated with a MVD of 13.5 Gy and a TTV{sub 30} of 28%. Cutoff values to avoid grade ≥3 leukopenia were MVD ≤23.9 Gy, TVV{sub 20} ≤56.0%, and TVV{sub 30} ≤52.1%. Conclusions: Hematologic toxicity is associated with greater RT doses to the TV during CRT for NSCLC. Sparing of the TV using advanced radiation techniques may improve tolerance of CRT and result in improved tolerance of concurrent chemotherapy.« less

Administration of Concurrent Vaginal Brachytherapy During Chemotherapy for Treatment of Endometrial Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagar, Himanshu; Boothe, Dustin; Parikh, Amar

2013-11-15

Purpose: To evaluate the tolerability and toxicity of administering vaginal brachytherapy (VB) concurrently during chemotherapy compared with the sequential approach for patients with endometrial cancer. Methods and Materials: A retrospective analysis of 372 surgically staged patients with endometrial cancer American Joint Committee on Cancer 2009 stages I to IV treated with adjuvant postoperative radiation therapy (RT) at our institution from 2001 to 2012 was conducted. All patients received VB + external beam RT (EBRT) + 6 cycles of adjuvant carboplatin- and paclitaxel-based chemotherapy. The VB mean dose was 15.08 Gy (range, 15-20 Gy), with 3 to 4 weekly applications, andmore » the EBRT mean dose was 45 Gy delivered with 3-dimensional or intensity modulated RT techniques. Hematologic, gastrointestinal (GI), and genitourinary (GU) toxicities were assessed by Common Toxicity Criteria (CTC) and compared between sequential and concurrent chemotherapy and VB schedules. Results: Among patients who received RT and adjuvant chemotherapy, 180 of 372 patients (48%) received RT sandwiched between cycles 3 and 4 of chemotherapy. A separate group of 192 patients (52%) were treated with VB during the first 3 cycles of chemotherapy, with a weekly application on nonchemotherapy days, and received the EBRT portion in a sandwiched fashion. Patients treated with VB during chemotherapy had a decreased overall treatment time by 4 weeks (P<.001; 95% confidence interval: 3.99-4.02) and sustained no difference in CTC-graded acute hematologic, GI, or GU toxicities in comparison with the patients treated with VB and chemotherapy in a sequential manner (P>.05). CTC grade 3 or 4 hematologic, GI, and GU toxicities were zero. Conclusions: VB during chemotherapy is well tolerated, decreases overall treatment time, and does not render more toxicity than the sequential regimen.« less

Hematologic Toxicity in Patients Treated With Postprostatectomy Whole-Pelvis Irradiation With Different Intensity Modulated Radiation Therapy Techniques Is Not Negligible and Is Prolonged: Preliminary Results of a Longitudinal, Observational Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cozzarini, Cesare, E-mail: cozzarini.cesare@hsr.it; Chiorda, Barbara Noris; Sini, Carla

Purpose: To address the thus-far poorly investigated severity and duration of hematologic toxicity from whole-pelvis radiation therapy (WPRT) in a cohort of chemo-naïve patients treated with postprostatectomy radiation therapy including WPRT with different intensity modulated radiation therapy (IMRT) techniques, doses, and fractionations. Methods and Materials: This analysis pertains to 125 patients (70 from a pilot study and 55 from an observational protocol) for whom 1 baseline and at least 3 subsequent blood samples (median 6), obtained at irradiation midpoint and end, and thereafter at 3, 6, and 12 months, were available. Patients were treated with adjuvant (n=73) or salvage intent; static-fieldmore » IMRT (n=19); volumetric modulated arc therapy (n=60) or helical Tomotherapy (n=46); and conventional (n=39) or moderately hypofractionated (median 2.35 Gy per fraction, n=86) regimens. The median 2-Gy equivalent dose (EQD2) to the prostatic bed was 70.4 Gy with a lymph-nodal planning target volume of 50.2 Gy. Clinical and dosimetric data were collected. Results: Both leukopenia and thrombocytopenia were significant (median nadir count 65% and 67% of baseline, respectively), with leukopenia also persisting (1-year median count 75% of baseline). Lymphopenia was the major contributor to the severity and 1-year persistence of leukopenia; all patients developed acute grade ≥1 lymphopenia (61% and 26% grade 2 and ≥3, respectively), whereas 1-year grade ≥2 lymphopenia was still present in 16%. In addition to an independent predictive role of corresponding baseline values, multivariable analyses highlighted that higher EQD2 doses to lymph nodal planning target volume increased risk of acute neutropenia and hypofractionation for acute thrombocytopenia. Of note, patients of older age were at higher risk for acute grade 2 lymphopenia, and interestingly, increased risk of grade >2 lymphopenia for those who smoked at least one year. No role for different IMRT techniques indicated. Conclusions: Leukopenia and lymphopenia after postprostatectomy WPRT were found to be less negligible and more prolonged than expected. A number of radiation-related and clinical factors favoring hematologic toxicity, whose awareness may be crucial when prescribing WPRT, in particular if concomitant to chemotherapy, were identified.« less

Comparative toxicity study on classical and modified version of Jawarish Jalinoos (a traditional Unani formulation) in rats.

PubMed

Husain, Gulam Mohammed; Ahmed, Syed Shoeb; Azhar, Misbahuddin; Siddiqui, Javed Inam; Waheed, Mohammad Abdul; Kazmi, Munawwar Husain

2017-03-01

Jawarish Jalinoos (JJ) is a classical semisolid traditional Unani formulation clinically used for the treatment of weakness of vital organs, liver, and stomach. Although JJ has been widely used clinically for several decades, no scientific report is available for its safety. JJ and its sugar-free tablet version (SFJJ; formulated to target diabetic population) were assessed for safety in rats. Ninety-day repeated dose oral toxicity study was performed as per the Organisation for Economic Co-operation and Development Guideline 408. JJ was orally administered at the dose of 2000 mg/kg bw/d, whereas SFJJ was orally administered at the doses of 506 mg/kg body weight (bw)/d, 1012 mg/kg bw/d, and 2024 mg/kg bw/d for 90 days. The animals were periodically observed for clinical signs of toxicity, mortality, morbidity, body weight changes, and feed consumption. At the end of the study, hematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight, and histological examination were performed. Treatment with SFJJ and JJ showed no significant differences in body weight gain, feed consumption, hematology, clinical biochemistry, and serum electrolytes. No gross pathological findings and differences in relative organ weights were observed between control and drug treated rats. Histological examination revealed no toxicologically significant abnormalities related with SFJJ or JJ treatment. The 90-day repeated dose oral toxicity study demonstrates that the no observed adverse effect level of SFJJ and JJ is greater than 2024 mg/kg bw/d and 2000 mg/kg bw/d (p.o.) in rats, respectively. Both formulations were found to be safe up to the tested dose levels and experimental conditions, and therefore safe for clinical use as specified in the literature.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knox, S J.; Goris, M L.; Tempero, M

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m{sup 2} (mean administered dose, 106.5-10.3 mCi/m{sup 2}) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients receivedmore » biotin-DOTA-labeled with 110 mCi/m{sup 2} Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.« less

Acute pulmonary and hematological effects of two types of particle surrogates are influenced by their elemental composition.

PubMed

Medeiros, N; Rivero, D H R F; Kasahara, D I; Saiki, M; Godleski, J J; Koutrakis, P; Capelozzi, V L; Saldiva, P H N; Antonangelo, L

2004-05-01

Several epidemiological studies have consistently demonstrated significant associations between ambient levels of particulate matter and lung injury and cardiovascular events with increased morbidity and mortality. Particle surrogates (PS), such as residual oil fly ash (ROFA), have been widely used in experimental studies aimed at characterizing the mechanisms of particle toxicity. Since PS composition varies depending on its source, studies with different types of PS may provide clues about the relative toxicity of the components generated by high-temperature combustion process. In this work, we have studied the effects of nasal instillation of increasing doses of different PS in mice: saline, carbon, and two types of particle surrogates. PS type A (PSA) was the ROFA collected from the waste incinerator of our university hospital; PS type B (PSB) was collected from the electrostatic precipitator of a large steel company and thus had an elevated metal content. After 24h, we analyzed hematological parameters, fibrinogen, bronchoalveolar lavage, bone marrow, and pulmonary histology. Nasal instillation of the two types of PS-induced leucopenia. PSB elicited a greater elevation of plasma fibrinogen levels. Bone marrow and pulmonary inflammatory changes were more intense for PSA. We concluded that the PS composition modulates acute inflammatory changes more significantly than the mass for these two types of PS.

Theranostics of Neuroendocrine Tumors.

PubMed

Lee, Sze Ting; Kulkarni, Harshad R; Singh, Aviral; Baum, Richard P

2017-10-01

Somatostatin receptor positron emission tomography/computed tomography using 68 Ga-labeled somatostatin analogs is the mainstay for the evaluation of receptor status in neuroendocrine tumors (NETs). This translates towards better therapy options, with increasing evidence of peptide receptor radionuclide therapy (PRRT) as the treatment of choice for advanced or progressive NETs. There are benefits in progression-free and overall survival as well as a significant improvement in clinical condition. In patients with progressive NETs, fractionated, personalized PRRT results in good therapeutic responses with no significant severe hematological and/or renal toxicity, thus improving quality of life.

Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial.

PubMed

Guo, Jun; Jin, Jie; Oya, Mototsugu; Uemura, Hirotsugu; Takahashi, Shunji; Tatsugami, Katsunori; Rha, Sun Young; Lee, Jae-Lyun; Chung, Jinsoo; Lim, Ho Yeong; Wu, Hsi Chin; Chang, Yen Hwa; Azad, Arun; Davis, Ian D; Carrasco-Alfonso, Marlene J; Nanua, Bhupinder; Han, Jackie; Ahmad, Qasim; Motzer, Robert

2018-05-22

The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.

Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer: A Meta-Analysis.

PubMed

Chen, Xingxing; Zou, Haizhou; Li, Huifang; Lin, Ruifang; Su, Meng; Zhang, Wenyi; Zhou, Yongqiang; Zhang, Ping; Hou, Meng; Deng, Xia; Zou, Changlin

2017-02-01

The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer. The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software. A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P >0.05). Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment.

PubMed

Gagnon, Jerome; Dervisis, Nikolaos G; Kitchell, Barbara E

2012-08-01

A retrospective study assessing treatment-related toxicities in tumor-bearing cats treated with temozolomide (TMZ) alone or in combination with doxorubicin was conducted. TMZ was administered orally once a day for 5 days every 3 weeks at a dose of 20 mg/cat. Tumor response was evaluated with standard World Health Organization criteria and toxicity was monitored using veterinary co-operative oncology group-common terminology criteria for adverse events (VCOG--CTCAE) criteria. Ten tumor-bearing cats with various types of malignancies were treated with TMZ-based chemotherapy. Eight cats were evaluable for response. Two cats achieved a complete response, one achieved stable disease and five achieved a partial response. Four grade III and one grade IV hematological toxicities, and one grade IV gastrointestinal toxicity were observed. Four cats were euthanased as a result of apparent toxicity. One cat was euthanased as a result of severe and prolonged myelosuppression with fever. Three were euthanased for grade III pleural and pericardial effusions. Effusion was seen in cats treated with higher cumulative dose of TMZ (P = 0.0046). Planned additional case accrual was discontinued because of unacceptable levels of toxicity despite evidence of efficacy in some of the cats. Additional investigation is needed to elucidate this unexpected apparent cumulative toxicity.

Use of KW-2189, a DNA minor groove-binding agent, in patients with hepatocellular carcinoma: a north central cancer treatment group (NCCTG) phase II clinical trial.

PubMed

Alberts, Steven R; Suman, Vera J; Pitot, Henry C; Camoriano, John K; Rubin, Joseph

2007-01-01

Hepatocellular carcinoma (HCC) is a common cancer in certain portions of the world. Currently no effective therapies exist for patients with advanced or metastatic HCC. KW-2189, a DNA minor groove-binding agent, has shown promising activity against HCC in preclinical evaluations. A phase II study was conducted to evaluate the activity of KW-2189 in patients with histologic or cytologic confirmed advanced or metastatic HCC who had no prior systemic therapy. Patients received KW-2189 at a dose of 0.5 mg/m2 administered on day 1 of a 6-week cycle. The primary endpoint of the trial was objective regression. Other endpoints included toxicity, disease-free survival, and overall survival. Due to hematologic toxicity the dose of KW-2189 was reduced to 0.375 mg/m2 after 11 patients had been enrolled into the trial. Due to continued significant hematologic toxicity in the next five patients enrolled at the lower dose the trial was closed to accrual. Two responses were seen in patients enrolled at the higher dose, including one sustained CR. KW-2189 showed evidence of anti-tumor activity in HCC. However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Further exploration of DNA minor groove-binding agents in the treatment of HCC appears warranted.

Hematological parameters on the effect of the jellyfish venom Cassiopea andromeda in animal models.

PubMed

Nabipour, Iraj; Mohebbi, Gholamhossein; Vatanpour, Hossein; Vazirizadeh, Amir

2017-04-01

For the first time, we previously recorded an enormous population of the Cassiopea andromeda jellyfish that had increased dramatically from Bushehr coasts of Iran. The sub-acute toxicity of the jellyfish venom in rat organs was correspondingly carried out. The data presented in this paper relate to the in vivo and in vitro hematological effects of this venomous species of jellyfish venom.

Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

PubMed

Vija Racaru, Lavinia; Sinigaglia, Mathieu; Kanoun, Salim; Ben Bouallègue, Fayçal; Tal, Ilan; Brillouet, Sévérine; Bauriaud-Mallet, Mathilde; Zerdoud, Slimane; Dierickx, Lawrence; Vallot, Delphine; Caselles, Olivier; Gabiache, Erwan; Pascal, Pierre; Courbon, Frederic

2018-05-21

This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for patient selection and treatment optimization.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Red Marrow-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody-Radionuclide Conjugate.

PubMed

Blakkisrud, Johan; Løndalen, Ayca; Dahle, Jostein; Turner, Simon; Holte, Harald; Kolstad, Arne; Stokke, Caroline

2017-01-01

Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. 177 Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity. Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the 177 Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of 177 Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity. Predosing with lilotomab reduces the RM-absorbed dose for 177 Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Clinico-hematological and micronuclear changes induced by cypermethrin in broiler chicks: Their attenuation with vitamin E and selenium.

PubMed

Sharaf, Summaira; Khan, Ahrar; Khan, Muhammad Zargham; Aslam, Faiza; Saleemi, Muhammad Kashif; Mahmood, Fazal

2010-07-01

This study was carried out on 90 one-day-old broiler chicks to know clinico-hematological alterations, DNA damage caused by cypermethrin (CY), and attenuation of toxic effects by vitamin E (Vit E) and selenium (Se). Birds were randomly divided into five equal groups. Groups 1-4 received CY (600mlkg(-1)b.wt) daily for 30 days by crop tubing. In addition to CY, groups 2, 3 and 4 received Vit E (150mgkg(-1)b.wt), Se (0.25mgkg(-1)b.wt), and Vit E (150mgkg(-1)b.wt)+Se (0.25mgkg(-1)b.wt), respectively. Group 5 served as control. Birds were monitored twice daily for clinical signs. They were weighed and blood samples were collected at experimental days 10, 20 and 30 for hematological studies. CY-treated birds showed more prominent signs of toxicity compared to CY+Vit E, CY+Se and CY+Vit E+Se birds. Body weight in groups 1-3 was significantly (P<0.05) smaller at days 20 and 30 when compared with the control group. Significantly (P<0.001) higher numbers of micronuclei appeared in chicks treated with CY compared to CY+Vit E- and CY+Se-treated birds. Significantly decreased total erythrocyte counts (TEC), hemoglobin (Hb) concentration and packed cell volume (PCV) in all treated groups were recorded. Treated birds suffered from macrocytic hypochromic anemia. Leukocytosis in early stage and later leucopenia was seen in treated birds. It can be concluded that CY induces toxic effects in broilers chicks; however, these toxic effects can be ameliorated by Vit E or Se. Combination of Vit E and Se was more effective to ameliorate toxic effects of cypermethrin.

A phase II study of combination chemotherapy with docetaxel and carboplatin for patients with advanced or metastatic non-small cell lung cancer.

PubMed

Kasahara, Kazuo; Kimura, Hideharu; Shibata, Kazuhiko; Araya, Tomoyuki; Sone, Takashi; Oribe, Yoshitaka; Furusho, Shiho; Kita, Toshiyuki; Shirasaki, Hiroki; Oribe, Yoshitaka; Yoshimi, Yuzo; Ueda, Akihito; Tachibana, Hideki; Shintani, Hiromoto; Mizuguchi, Masayuki; Nishi, Kohichi; Fujimura, Masaki; Nakao, Shinji

2006-01-01

The aim of this phase II study was to evaluate the efficacy of combination chemotherapy consisting of docetaxel and carboplatin in patients with inoperable non-small cell lung cancer (NSCLC). For this multicenter phase II study, the eligibility criteria included histologically or cytologically proven inoperable NSCLC, measurable lesions, Eastern Cooperative Oncology Group performance status (PS) 0-2, adequate organ and bone marrow functions, and written informed consent. Patients received 60 mg/m2 of docetaxel and carboplatin (target AUC 5.5) on day 1 every 3 weeks until disease progression. The primary end-point of this study was response rate and the secondary end-points were toxicities, time to progression and overall survival. A total of 40 patients were enrolled and 39 patients were eligible. A complete response and partial response were observed in 1 and 13 patients, respectively. An objective response rate was 35.9% (95% confidential interval [CI] 20.8-51.0%). The median time to progression was 5.2 months and the median overall survival was 12.0 months. The 1- and 2-year survival rates were 53.8% and 25.1%, respectively. The major toxicities were leukocytopenia and neutropenia. Grade 3 or 4 thrombocytopenia was rare and non-hematological toxicities were generally mild. Grade 3 non-hematological toxicities were observed in 6 patients (2 with nausea and vomiting, 1 with diarrhea, 1 with elevated transaminase levels, 1 with allergic reaction and 1 with edema). No grade 4 non-hematological toxicities were observed. Docetaxel and carboplatin combination chemotherapy was well tolerated and active in Japanese patients with advanced or metastatic NSCLC.

Gemcitabine-oxaliplatin (GEMOX) for epithelial ovarian cancer patients resistant to platinum-based chemotherapy.

PubMed

Elshebeiny, Mohamed; Almorsy, Walid

2016-09-01

Patients with platinum-resistant epithelial ovarian cancer (EOC) experience poor outcome. Currently, no clearly superior management strategy exists for platinum-resistant EOC patients. Analyze the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) in platinum resistant EOC patients. Thirty-two patients with platinum-based resistant EOC were included. Studied patients had received GEM at the dose of 1000mg/m(2) on days 1 and 8 and OX 100mg/m(2) on day 1, administered over 2h 30min after GEM infusion of 3week treatment cycle. In the evaluation of tumor response, none of patients had achieved CR while PR, SD, were observed in 7 (21.9%), 9 (28.1%) respectively, clinical benefit (CR+PR+SD) was recorded in 50% of patients while PD was observed in 16 (50%) patients. In regard to survival, the median value of OS was 10.5months (range, 2.2-17.5months). The median value of PFS was 6.37months (range, 1-17.5months). The one-year OS rate was 34.4% and the one-year PFS rate was 12.5%. Concerning hematological toxicity grade 3 neutropenia was recorded in 4 (12.5%) patients while grade 4 febrile neutropenia was recorded in 2 (6.3%) patients and grade 4 anemia was represented by 3.1%. Grade 1-2 fatigue was the most common non-hematological toxicity and represented by 65.6% of patients. Grade 3 non hematological toxicity was recorded with nausea/vomiting and hepatic toxicity represented by 3.1% for both. The GEMOX combination is a regimen with a moderate therapeutic efficacy and tolerable toxic side effects in patients with platinum-resistant EOC. Copyright © 2016. Production and hosting by Elsevier B.V.

Chemotherapy-related leukopenia as a biomarker predicting survival outcomes in locally advanced cervical cancer.

PubMed

Bogani, Giorgio; Sabatucci, Ilaria; Maltese, Giuseppa; Lecce, Francesca; Signorelli, Mauro; Martinelli, Fabio; Chiappa, Valentina; Indini, Alice; Leone Roberti Maggiore, Umberto; Borghi, Chiara; Fucà, Giovanni; Ditto, Antonino; Raspagliesi, Francesco; Lorusso, Domenica

2017-01-01

To investigate the impact of hematologic toxicity and leukopenia in locally advanced cervical cancer patients undergoing neoadjuvant chemotherapy (NACT). Data of consecutive patients undergoing platinum-based NACT followed by surgery were retrospectively searched in order to evaluate the impact of chemotherapy-related toxicity on survival outcomes. Toxicity was graded per the Common Terminology Criteria for Adverse Events (CTCAEv.4.03). Survival outcomes were evaluated using Kaplan-Meir and Cox hazard models. Overall, 126 patients were included. Among those, 94 (74.6%) patients experienced grade2+ hematologic toxicity; while, grade2+ non-hematologic toxicity occurred in 11 (8.7%) patients. After a median follow-up of 37.1 (inter-quartile range, 12-57.5) months, 21 (16.6%) patients experienced recurrence. Via multivariate analysis, no factor was independently associated with disease-free survival; while a trend toward worse prognosis was observed for patients experiencing grade2+ leukopenia at cycle-3 (HR:3.13 (95%CI: 0.94, 10.3); p=0.06). Similarly, grade2+ leukopenia (HR:9.98 (95%CI: 1.14, 86.6); p=0.03), lymph-node positivity (HR:14.6 (95%CI:1.0, 214.4); p=0.05) and vaginal involvement (HR:5.81 (95%CI:1.43, 23.6); p=0.01) impacted on overall survival, at multivariate analysis. Magnitude of leukopenia correlated with survival (p<0.001). Although, our data have to be confirmed by prospective investigations, the present study shows an association between the occurrence of leukopenia and survival outcomes. NACT-related immunosuppression might reduce the response against the tumor, thus promoting cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of waterborne Fe(II) on juvenile turbot Scophthalmus maximus: analysis of respiratory rate, hematology and gill histology

NASA Astrophysics Data System (ADS)

Wu, Zhihao; You, Feng; Liu, Hongjun; Liu, Mengxia; Li, Jun; Zhang, Peijun

2012-03-01

The concentration of Fe(II) is high in some groundwater supplies used in turbot culture, and the toxicity of waterborne Fe(II) is unknown. We investigated the stress responses of juvenile turbot, Scophthalmus maximus, exposed to Fe(II) of different concentrations (0.01, 0.05, 0.1, 0.5, 1, and 2 mg/L) for 1, 7, 14, and 28 d, under the same ambient conditions of other parameters. Changes in respiratory rate, hematological parameters, and gill structure were determined. The results show that waterborne Fe(II) did not cause severe hematological perturbation to turbot. A low-medium Fe(II) concentration (lower than 0.1 mg/L) could boost the respiratory rate, and caused no or very limited damage to fish. A high Fe(II) concentration (0.1 mg/L or higher), however, caused gill damage, such as vacuoles in branchial lamellae, epithelial necrosis, and hypertrophy of epithelial cells, and even death after extended exposure time. Therefore, excess waterborne Fe(II) and long-term exposure to Fe(II) could be responsible for poor growth and high mortality of turbot in culture. The concentration of waterborne Fe(II) in turbot culture should be kept below 0.1 mg/L.

PACSIN2 polymorphism is associated with thiopurine-induced hematological toxicity in children with acute lymphoblastic leukaemia undergoing maintenance therapy.

PubMed

Smid, Alenka; Karas-Kuzelicki, Natasa; Jazbec, Janez; Mlinaric-Rascan, Irena

2016-07-25

Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.

Antitumoral activity and toxicity of PEG-coated and PEG-folate-coated pH-sensitive liposomes containing ¹⁵⁹Gd-DTPA-BMA in Ehrlich tumor bearing mice.

PubMed

Soares, Daniel Crístian Ferreira; Cardoso, Valbert Nascimento; de Barros, André Luís Branco; de Souza, Cristina Maria; Cassali, Geovanni Dantas; de Oliveira, Mônica Cristina; Ramaldes, Gilson Andrade

2012-01-23

In the present study, PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the ¹⁵⁹Gd-DTPA-BMA were prepared and radiolabeled through neutron activation technique, aiming to study the in vivo antitumoral activity and toxicity on mice bearing a previously-developed solid Ehrlich tumor. The treatment efficacy was verified through tumoral volume increase and histomorphometry studies. The toxicity of formulations was investigated through animal weight variations, as well as hematological and biochemical tests. The results showed that after 31 days of treatment, animals treated with radioactive formulations had a lower increase in tumor volume and a significantly higher percentage of necrosis compared with controls revealed by histomorphometry studies. Furthermore, mice treated with radioactive formulations exhibited lower weight gain without significant hematological or biochemical changes, except for toxicity to hepatocytes which requires more detailed studies. From the results obtained to date, we believe that the radioactive formulations can be considered potential therapeutic agents for cancer. Copyright © 2011 Elsevier B.V. All rights reserved.

Hematologic Nadirs During Chemoradiation for Anal Cancer: Temporal Characterization and Dosimetric Predictors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Andrew Y.; Golden, Daniel W.; Bazan, Jose G.

Purpose: Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity. Methods and Materials: Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood countsmore » at a standardized time point to identify predictors of initial blood count nadirs. Results: Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P=.02), grade 3+ neutropenia (33% vs 8%, P=.04), and grade 2+ thrombocytopenia (32% vs 7%, P=.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 (P<.1). Conclusions: Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total “marrow reserve” can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.« less

Health risks of genetically modified foods.

PubMed

Dona, Artemis; Arvanitoyannis, Ioannis S

2009-02-01

As genetically modified (GM) foods are starting to intrude in our diet concerns have been expressed regarding GM food safety. These concerns as well as the limitations of the procedures followed in the evaluation of their safety are presented. Animal toxicity studies with certain GM foods have shown that they may toxically affect several organs and systems. The review of these studies should not be conducted separately for each GM food, but according to the effects exerted on certain organs it may help us create a better picture of the possible health effects on human beings. The results of most studies with GM foods indicate that they may cause some common toxic effects such as hepatic, pancreatic, renal, or reproductive effects and may alter the hematological, biochemical, and immunologic parameters. However, many years of research with animals and clinical trials are required for this assessment. The use of recombinant GH or its expression in animals should be re-examined since it has been shown that it increases IGF-1 which may promote cancer.

A Review on the Effect of Traditional Chinese Medicine Against Anthracycline-Induced Cardiac Toxicity

PubMed Central

Yang, Xinyu; Liu, Nian; Li, Xinye; Yang, Yihan; Wang, Xiaofeng; Li, Linling; Jiang, Le; Gao, Yonghong; Tang, Hebin; Tang, Yong; Xing, Yanwei; Shang, Hongcai

2018-01-01

Anthracyclines are effective agents generally used to treat solid-tumor and hematologic malignancies. The use of anthracyclines for over 40 years has improved cancer survival statistics. Nevertheless, the clinical utility of anthracyclines is limited by its dose-dependent cardiotoxicity that adversely affects 10–30% of patients. Anthracycline-induced cardiotoxicity may be classified as acute/subacute or chronic/late toxicity and leads to devastating adverse effects resulting in poor quality of life, morbidity, and premature mortality. Traditional Chinese medicine has a history of over 2,000 years, involving both unique theories and substantial experience. Several studies have investigated the potential of natural products to decrease the cardiotoxic effects of chemotherapeutic agents on healthy cells, without negatively affecting their antineoplastic activity. This article discusses the mechanism of anthracycline-induced cardiotoxicity, and summarizes traditional Chinese medicine treatment for anthracycline-induced heart failure (HF), cardiac arrhythmia, cardiomyopathy, and myocardial ischemia in recent years, in order to provide a reference for the clinical prevention and treatment of cardiac toxicity. PMID:29867456

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement.

PubMed

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). In vivo toxicity studies were performed in male balb 'C' mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mercado-Feliciano, Minerva; Cora, Michelle C.; Witt, Kristine L.

2012-09-01

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/daymore » BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents. -- Highlights: ► Mice and rats were dosed with black cohosh extract for 90 days starting at weaning. ► Hematological changes were consistent with a non-regenerative macrocytic anemia. ► Peripheral micronucleated red blood cell frequencies increased. ► Puberty was delayed 2.9 days in rats. ► No estrogenic/anti-estrogenic activity was seen in the uterotrophic assay.« less

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.

PubMed

Brown, Jennifer R; Barrientos, Jacqueline C; Barr, Paul M; Flinn, Ian W; Burger, Jan A; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W; Rai, Kanti; O'Brien, Susan

2015-05-07

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. © 2015 by The American Society of Hematology.

77 FR 58493 - Flumioxazin; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-21

... toxic effects associated with flumioxazin include anemia as well as effects on the liver and the... rabbit studies. Hematologic (hematopoietic) effects of anemia were noted in rats, consisting of...

The Course of Toxicity in the Pregnant Mouse after Exposure to the Cyanobacterial Toxin, Cylindrospermopsin: Clinical Effects, Serum Chemistries, Hematology and Histopathology

EPA Science Inventory

Cylindrospermopsin (CYN) is a toxin produced by a wide variety of fresh water cyanobacterial species worldwide and induces significant adverse effects in both livestock and humans. This study investigated the course of CYN-induced toxicity in pregnant mice exposed during either t...

Concurrent chemoradiotherapy with elective lymph node irradiation for esophageal cancer: a systemic review and pooled analysis of the literature.

PubMed

Du, Dexi; Song, Tao; Liang, Xiaodong; Fang, Min; Wu, Shixiu

2017-02-01

Concurrent chemoradiotherapy (CCRT) has been accepted as the standard non-surgical treatment for esophageal cancer. However, no consistent conclusions have been reached whether elective lymph node irradiation (ENI) should be delivered. Therefore, we performed a systematic review and pooled analysis to evaluate the value of CCRT with ENI. A literature search based on PubMed, Embase and Google Scholar was carried out and all of the studies were evaluated carefully regarding with survival outcomes, response rates, patterns of failure rates and acute/late toxicities. Twenty-two studies were identified based on the criteria: median overall survival time was 21.0 months; pooled response rates were 56.8% (CR) and 85.8% (CR+PR), respectively; residual disease rate, local-regional recurrence rate, distant failure rate and both (local-regional recurrence plus distant failure) rate was 28%, 21%, 11%, and 7%, respectively; hematologic toxicities were the most sever acute toxicities and esophagus-related toxicity was the most common radiation-related toxicity both in acute (15.7%) and late (6.2%) phase. In conclusion, ENI is feasible with acceptable toxicities in esophageal carcinoma and the efficacy should be verified in randomized trials. © 2016 International Society for Diseases of the Esophagus.

Sex differences in the toxicity of polyethylene glycol-coated gold nanoparticles in mice

PubMed Central

Chen, Jie; Wang, Hao; Long, Wei; Shen, Xiu; Wu, Di; Song, Sha-Sha; Sun, Yuan-Ming; Liu, Pei-Xun; Fan, Saijun; Fan, Feiyue; Zhang, Xiao-Dong

2013-01-01

Gold nanoparticles have received wide interest in disease diagnosis and therapy, but one of the important issues is their toxicological effects in vivo. Sex differences in the toxicity of gold nanoparticles are not clear. In this work, body weight, organ weight, hematology, and biochemistry were used to evaluate sex differences in immune response and liver and kidney damage. Pathology was used to observe the general toxicity of reproductive organs. The immune response was influenced significantly in female mice, with obvious changes in spleen and thymus index. Hematology results showed that male mice treated with 22.5 nm gold nanoparticles received more significant infection and inflammation than female mice. Meanwhile, the biochemistry results showed that 4.4 and 22.5 nm gold nanoparticles caused more significant liver damage in male mice than female mice, while 22.5, 29.3, and 36.1 nm gold nanoparticles caused more significant kidney damage in female mice than male mice. No significant toxicological response was found in the reproductive system for female or male mice. It was found that gold nanoparticles caused more serious liver toxicity and infection in male mice than female mice. These findings indicated that sex differences may be one of the important elements for in vivo toxicity of gold nanoparticles. PMID:23861586

Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae) in Swiss Mice

PubMed Central

Freire Rocha Caldas, Germana; Araújo, Alice Valença; Albuquerque, Giwellington Silva; Silva-Neto, Jacinto da Costa; Costa-Silva, João Henrique; de Menezes, Irwin Rose Alencar; Leite, Ana Cristina Lima; da Costa, José Galberto Martins; Wanderley, Almir Gonçalves

2013-01-01

Hyptis martiusii Benth. (Lamiaceae) is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM). Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg) for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice. PMID:24151521

Past, Present and Emerging Toxicity Issues for Jet Fuel

DTIC Science & Technology

2011-01-01

Statistically significant dominant lethal effects were not observed for either mice or rats (Air Force, 1978). However, because of the small sample...Adams, M.M., 2004. Immunological and hematological effects observed in B6C3F1 mice exposed to JP-8 jet fuel for 14 days. J. Toxicol. Environ. Health A...acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with

Safety assessment of ethanolic extract of Olea europaea L. leaves after acute and subacute administration to Wistar rats.

PubMed

Guex, Camille Gaube; Reginato, Fernanda Ziegler; Figueredo, Kássia Caroline; da Silva, Andreia Regina Haas da; Pires, Fernanda Brum; Jesus, Roberta da Silva; Lhamas, Cibele Lima; Lopes, Gilberti Helena Hübscher; Bauermann, Liliane de Freitas

2018-06-01

Olea europaea L., popularly known as olive, is a plant widely used worldwide. Its leaves, fruit and oil are extensively consumed and present important pharmacological properties. However, studies regarding the toxicity of olive leaves are still limited in the literature. Therefore, the aim of the study was to investigate acute and subacute oral toxicities of the ethanolic extract of olive leaves (EEO) in Wistar rats through histopathology and biochemical and hematological parameters. Acute toxicity was assessed using a single dose of 2000 mg/kg of EEO administered by oral gavage to male and female rats. To assess subacute toxicity, EEO was administered during 28 days at different doses (100, 200 and 400 mg/kg) to male and female rats. At the end of the experiments, the liver and kidney were removed and examined microscopically, and blood was collected for hematological and biochemical parameters. A single dose of 2000 mg/kg did not induce mortality or any signs of toxicity among the animals treated. Animals exposed to EEO during 28 days did not present sign of abnormalities. Results demonstrated that EEO did not induce toxicity after exposure to single and repeated doses. However, more studies are needed to fully understand implications for human safety. Copyright © 2018 Elsevier Inc. All rights reserved.

The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks.

PubMed

Grabarevic, Z; Tisljar, M; Artukovic, B; Bratulic, M; Dzaja, P; Seiwerth, S; Sikiric, P; Peric, J; Geres, D; Kos, J

1997-01-01

We describe the effects of nitric oxide (NO) agonists and antagonists and the influence of a novel organoprotective pentadecapeptide BPC 157, on the development of pulmonary hypertension syndrome and tissue lesions in chicks. Acute toxicity, which includes single dose application of saline (1 mL intraperitoneally (i.p.)), BPC 157 (10 micrograms/kg bw), L-NAME (NO antagonist, doses 50, 100, 150 mg/kg bw) and L-arginine (NO agonist/100 mg/kg bw with their combination L-NAME + BPC 157; L-NAME + L-arginine) was investigated. In this experiment pathohistological examination of the spleen, heart, liver and lungs and hematological analysis was conducted. In the chronic toxicity experiment, the animals were treated daily for 5 weeks with L-NAME (10 mg/kg bw), L-arginine (100 mg/kg bw), BPC 157 (10 micrograms/kg bw) and their combinations (L-NAME + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine) i.p. Seven animals from each group, including controls (saline 1 mL i.p.) were killed every week. Application of L-NAME caused pulmonary hypertension syndrome (PHS) in the treated chicks, which was prevented by the simultaneous application of L-arginine and BPC 157. Pathohistological examination of both acute and chronic toxicity revealed that L-NAME caused severe tissue damage (myocardial and hepatic cell necrosis, necrosis of the lymphoid cells in the spleen) while L-arginine provoked predominantly congestion, edema and hemorrhages in all organs. The effect of L-NAME was successfully inhibited by the application of L-arginine and BPC 157 but the latter substance did not cause any tissue or organ damage. Hematological analysis shows significant hemoglobin and leukocyte number decrease in the L-NAME-treated groups of chicks.

Protective effect of thymoquinone against diazinon-induced hematotoxicity, genotoxicity and immunotoxicity in rats.

PubMed

Danaei, Gholam Hassan; Karami, Mohammad

2017-10-01

Several studies have shown that oxidative stress and cell damage can occur in the very early stages of diazinon (DZN) exposure. The present study was designed to determine the beneficial effect of thymoquinone (Thy), the main component of Nigella sativa (black seed or black cumin) against DZN immunotoxicity, hematotoxicity and genotoxicity in rats. In the present experimental study, 48 male Wistar rats were randomly divided into six groups, (eight per group) as follows: control (receiving corn oil as the DZN solvent), DZN (20mg/kg), Thy (10mg/kg), Thy (2.5mg/kg)+DZN, Thy (5mg/kg)+DZN and Thy (10mg/kg)+DZN. After four weeks of treatment, the hematological parameters of red blood cells (RBCs), white blood cells (WBCs), hemoglobin (Hb), hematocrit (Hct) and platelets (PLTs) were evaluated. The evaluation of genotoxicity was carried out using the micronucleus assay. For measurement of cytokine production, interferon gamma (IFN-γ), interleukin 10 (IL10) and interleukin 4 (IL4) were chosen as immunotoxicity indicators of DZN toxicity. DZN was found to decrease RBCs, WBCs, Hb, Hct, PLTs, butyrl- and acetyl-cholinesterase activity and I FN-γ and increased the micronucleus indices of IL10 and IL4 as compared with the control group. Treatment with Thy reduced DZN hematotoxicity and immunotoxicity, but, significantly, did not prevent genotoxicity. This study showed that Thy (without the significant effect on genotoxicity) decreased the hematological toxicity, immunotoxicity and butyrl and acetyl cholinesterase activity induced by DZN. The success of Thy supplementation against DZN toxicity can be attributed to the antioxidant effects of its constituents. Copyright © 2017. Published by Elsevier B.V.

The challenging aspects of managing adolescents and young adults with Hodgkin's lymphoma.

PubMed

Jachimowicz, Ron D; Engert, Andreas

2014-01-01

Cancer in the adolescent and young adult (AYA) is the second leading cause of nonaccidental death with hematological malignancies spiking during this period. Treatment of AYAs with hematological malignancies usually follows either pediatric or adult protocols with sufficient information lacking on subgroup analyses regarding course and outcome. In this review we will outline up-to-date treatment possibilities for AYAs diagnosed with Hodgkin's lymphoma. Early and late toxicities will be addressed and future directions of research suggested. © 2014 S. Karger AG, Basel.

Acute and subchronic toxicities of QX100626, a 5-HT4 receptor agonist, in rodents and Beagle dogs.

PubMed

Zhang, Xiaofang; Yuan, Bojun; Mao, Yu; Dai, Xiaoyu; Zhang, Xiaodong; Lu, Guocai

2014-10-01

Serotonin 5-hydroxytryptamine 4(5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0mg/kgb.w., and the severe toxic dose was more than 300mg/kgb.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20mg/kg and 10mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Oxaliplatin-induced Oxidative Stress Provokes Toxicity in Isolated Rat Liver Mitochondria.

PubMed

Tabassum, Heena; Waseem, Mohammad; Parvez, Suhel; Qureshi, M Irfan

2015-11-01

Oxaliplatin is a widely employed platinum-derived chemotherapeutic agent commonly used for the treatment of colorectal cancer. Unfortunately, the benefit of this important drug is compromised by severe side effects such as neuropathy, ototoxicity, gastrointestinal toxicity, and hematological toxicity. Recently, few studies have also suggested the occurrence of hepatotoxicity in oxaliplatin-treated patients. Mitochondria have emerged as targets for anticancer drugs in various kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. Oxidative stress is a well-established biomarker of mitochondrial toxicity. The purpose of this study was to investigate the dose-dependent damage caused by oxaliplatin on isolated liver mitochondria under in vitro conditions. The study was conducted in mitochondria isolated from liver of Wistar rats. Oxaliplatin was incubated with mitochondria in a dose-dependent manner under in vitro conditions. Oxidative stress indexes, non-enzymatic and enzymatic antioxidants were evaluated, looking at the overall armamentarium against the toxicity induced by oxaliplatin. Oxaliplatin caused a significant rise in the mitochondrial oxidative stress indexes lipid peroxidation and protein carbonyl. Alterations in the levels of non-enzymatic antioxidants and activities of enzymatic antioxidants were also observed. Oxidative stress plays an important role in the mitochondrial toxicity of oxaliplatin. The integrity of the hepatic tissue is compromised by the reactive oxygen species-mediated lipid peroxidation and protein carbonyl formation. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement

PubMed Central

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement. PMID:23087514

Higher Dose Imatinib for Children With De Novo Chronic Phase Chronic Myelogenous Leukemia: A Report From the Children’s Oncology Group

PubMed Central

Champagne, Martin A.; Fu, Cecilia H.; Chang, Myron; Chen, Helen; Gerbing, Robert B.; Alonzo, Todd A.; Cooley, Linda D.; Heerema, Nyla A.; Oehler, Vivian; Wood, Charlotte; French, Mary Ellen; Arceci, Robert J.; Smith, Franklin O.; Bernstein, Mark L.

2016-01-01

Purpose To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML). Methods This was an open label, multi-center phase II clinical trial. Courses were defined as consecutive 28-day intervals. Oral imatinib was administered daily at 340 mg/m2 without interruption in the absence of toxicity. Results Fifty-one children received 978 28-day courses of imatinib. The most common toxicities encountered were hematologic. Forty-one patients (80%) achieved a complete hematologic response by the end of course 2. Nineteen children (38%) obtained a complete cytogenetic response (CCyR) at the end of course 3. Overall, 72% achieved CCyR at a median time of 5.6 months. The rate of complete molecular response (>3 log reduction) was 27%. Progression-free and overall survival at 3 years were 72% ± 6.4% and 92% ± 3.9%, respectively. Conclusions Daily oral imatinib at a dose of 340 mg/m2 is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. PMID:21465636

Sub-chronic safety evaluation of aqueous extract of Alangium salvifolium (L.f.) Wangerin leaves in rats.

PubMed

Kapoor, Bhupinder; Kaur, Gagandeep; Gupta, Mukta; Gupta, Reena

2017-01-01

Conventionally, the juice and extract of Alangium salvifolium leaves have been used for the treatment of diabetes, wound healing, dog bite, and as a poultice in rheumatism. To carry out the sub-chronic toxicity and thereafter safety evaluation of A. salvifolium leaves. The aqueous extract of A. salvifolium leaves was administered orally at the doses of 200, 400, and 800 mg/kg/day for 90 days. All the animals were observed daily for general behavior, changes in body weight, food, and water consumption. At the end of the treatment period, biochemical and hematological parameters were analyzed; and the animals were sacrificed for histopathological examination of heart, lungs, liver, and kidney. The general behavior and water intake were normal in all the rats. The increase in body weight was observed in female rats of all the groups while body weight was decreased in high dose group animals of both sexes. Hematological parameters were not disturbed by the continuous use of extract. A significant decrease in glucose level was observed in intermediate- and high-dose group animals while urea and creatinine level were significantly high in animals of high-dose group. Although histopathological examination of most of the organs exhibited no structural changes, some tubal damage in kidneys was observed in high-dose group animals. The high dose of extract has shown mild signs of toxicity on kidney function test, but no toxic response was observed on hematological and liver biochemical parameters. The extract also exhibited hypoglycemic potential.

Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients.

PubMed

Riccardi, Anna; Mazzarella, Giorgio; Cefalo, Graziella; Garrè, Maria Luisa; Massimino, Maura; Barone, Carlo; Sandri, Alessandro; Ridola, Vita; Ruggiero, Antonio; Mastrangelo, Stefano; Lazzareschi, Ilaria; Caldarelli, Massimo; Maira, Giulio; Madon, Enrico; Riccardi, Riccardo

2003-12-01

To characterize and compare pharmacokinetic parameters in children and adults treated with temozolomide (TMZ) administered for 5 days in three doses daily, and to evaluate the possible relationship between AUC values and hematologic toxicity. TMZ pharmacokinetic parameters were characterized in pediatric and adult patients with primary central nervous system tumors treated with doses ranging from 120 to 200 mg/m2 per day, divided into three doses daily for 5 days. Plasma levels were measured over 8 h following oral administration in a fasting state. A total of 40 courses were studied in 22 children (mean age 10 years, range 3-16 years) and in 8 adults (mean age 30 years, range 19-54 years). In all patients, a linear relationship was found between systemic exposure (AUC) and increasing doses of TMZ. Time to peak concentration, elimination half-life, apparent clearance and volume of distribution were not related to TMZ dose. No differences were seen among TMZ C(max), t(1/2), V(d) or CL/F in children compared with adults. Intra- and interpatient variability of systemic exposure were limited in both children and adults. No statistically significant differences were found between the AUCs of children who experienced grade 4 hematologic toxicity and children who did not. No difference appears to exist between pharmacokinetic parameters in adults and children when TMZ is administered in three doses daily. Hematologic toxicity was not related to TMZ AUC. AUC measurement does not appear to be of any use in optimizing TMZ treatment.

Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Kathy; Cummings, Bernard J.; Lindsay, Patricia

Purpose: A prospective cohort study was conducted to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for anal and perianal cancer. Methods and Materials: From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicitymore » was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation. Results: Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus—positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores. Conclusion: IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.« less

Toxicities of chimeric antigen receptor T cells: recognition and management

PubMed Central

Brudno, Jennifer N.

2016-01-01

Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy. PMID:27207799

Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias.

PubMed

Schaffner, A; Schaffner, M

1995-10-01

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).

[Effect of Vimang in HIV/AIDS patients].

PubMed

Gil del Valle, Lizette; Serrano López, Teresita; Calderón Fuentes, Odalys; Núñez Sánchez, Felicita; Tápanes Peraza, Rolando D; Pérez Avila, Jorge

2010-01-01

the oxidative stress (OS) has been recognized as a co-factor of HIV infection evolution to AIDS condition. to evaluate the possible antioxidant effect and the impact on the functioning of several systems in the body, resulting in the toxicological safety of Vimang use. sixty eight HIV-seropositive patients were double-blind randomized in two groups; the first was supplied with Vimang during six months and the other with placebo. Redox condition and the biochemical indexes of the hematological, renal and hepatic functions were measured. Also, dietary intake was assessed through surveys administered for 7 days at the beginning and at the end of the study. there were statistically significant differences between the groups regarding positive change in redox figures in Vimang group compared to those of the placebo group. No significant difference was found either in the evaluated dietary intake indexes or in the biochemical indexes of the renal, hematological and hepatic functions at the end of the study. Vimang antioxidant effect was shown, without any toxic influence during the six month-study conducted in HIV/AIDS patients.

Evaluation of locally established reference intervals for hematology and biochemistry parameters in Western Kenya.

PubMed

Odhiambo, Collins; Oyaro, Boaz; Odipo, Richard; Otieno, Fredrick; Alemnji, George; Williamson, John; Zeh, Clement

2015-01-01

Important differences have been demonstrated in laboratory parameters from healthy persons in different geographical regions and populations, mostly driven by a combination of genetic, demographic, nutritional, and environmental factors. Despite this, European and North American derived laboratory reference intervals are used in African countries for patient management, clinical trial eligibility, and toxicity determination; which can result in misclassification of healthy persons as having laboratory abnormalities. An observational prospective cohort study known as the Kisumu Incidence Cohort Study (KICoS) was conducted to estimate the incidence of HIV seroconversion and identify determinants of successful recruitment and retention in preparation for an HIV vaccine/prevention trial among young adults and adolescents in western Kenya. Laboratory values generated from the KICoS were compared to published region-specific reference intervals and the 2004 NIH DAIDS toxicity tables used for the trial. About 1106 participants were screened for the KICoS between January 2007 and June 2010. Nine hundred and fifty-three participants aged 16 to 34 years, HIV-seronegative, clinically healthy, and non-pregnant were selected for this analysis. Median and 95% reference intervals were calculated for hematological and biochemistry parameters. When compared with both published region-specific reference values and the 2004 NIH DAIDS toxicity table, it was shown that the use of locally established reference intervals would have resulted in fewer participants classified as having abnormal hematological or biochemistry values compared to US derived reference intervals from DAIDS (10% classified as abnormal by local parameters vs. >40% by US DAIDS). Blood urea nitrogen was most often out of range if US based intervals were used: <10% abnormal by local intervals compared to >83% by US based reference intervals. Differences in reference intervals for hematological and biochemical parameters between western and African populations highlight importance of developing local reference intervals for clinical care and trials in Africa.

ω-3 Fatty Acids Reduce Chemotherapy-Induced Hematological Toxicity by Bone Marrow Stimulation in Mice.

PubMed

Murakami, Kohei; Miyata, Hiroshi; Miyazaki, Yasuhiro; Makino, Tomoki; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Yamasaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

2017-07-01

ω-3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω-3 fatty acids on chemotherapy-induced hematological toxicities. Mice that had consumed either an ω-3-rich or an ω-3-poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω-3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω-3-rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω-3-rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF-1) were significantly higher in bone marrow supernatants from mice that consumed the ω-3-rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω-3 fatty acids was significantly lower than in PBMCs cultured in control medium. ω-3-Rich diets reduced chemotherapy-induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF-1 in the bone marrow.

Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats.

PubMed

Diniz Rosa, Damiana; Gouveia Peluzio, Maria do Carmo; Pérez Bueno, Tania; Vega Cañizares, Ernesto; Sánchez Miranda, Lilian; Mancebo Dorbignyi, Betty; Chong Dubí, Dainé; Espinosa Castaño, Ivette; Marcin Grzes Kowiak, Lukasz; Fortes Ferreira, Célia Lucia de Luces

2014-06-01

Kefir is obtained by fermentation of milk with complex microbial populations present in kefir grains. Several health-promoting benefits have been attributed to kefir consumption. The objective of this work was to conduct a subchronic toxicity study, offering the rats normal or high-doses of kefir and evaluating growth, hematology and blood chemistry, as well as assessing bacterial translocation and the integrity of the intestinal mucosa of animals. Wistar rats were randomly divided into three groups (n = 6/group): control group received 0.7 mL of water, kefir group received 0.7 mL/day of kefir, (normodose), and Hkefir group received 3.5 mL/day of kefir (fivefold higher dose). Feeding was carried out by gavage. The animals were housed in individual cages and maintained under standard conditions for 4 weeks. The normodose and high-dose of kefir supplementation did not harm the animals since growth, hematology and blood chemistry in rats, as well as the potential pathogenicity in tissues were within normal limits, demonstrating that consumption of normodose and highdose of kefir are safe. In addition, administration of the normodose of kefir reduced cholesterol levels and improved the intestinal mucosa of the rats. These results demonstrate that the consumption of kefir is safe. Importantly, while damages are not seen for the high-dose, the normodose consumption is recommended due to the pronounced beneficial effects, as safety is concerned. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Sub-acute toxicity of cultured mycelia of himalayan entomogenous fungus Cordyceps sinensis (Berk.) Sacc. in rats.

PubMed

Meena, Harsahay; Singh, Kshetra Pal; Negi, Prem Sing; Ahmed, Zakwan

2013-05-01

Oral administration of laboratory cultured mycelia powder of C. sinensis did not show any sign of toxicity as no significant change was observed in organ weight and serological parameters in rats. However, there was a significant increase in food intake, body weight gain and hematological parameters like WBC, RBC, Hb and lymphocytes in treated groups. Histopathology of vital organs also supported the non toxic effect of C. sinensis. The results conclude that laboratory cultured mycelia powder of C. sinensis is safe and non toxic up to 2 g/kg body weight dose.

Analysis of quantitative data obtained from toxicity studies showing non-normal distribution.

PubMed

Kobayashi, Katsumi

2005-05-01

The data obtained from toxicity studies are examined for homogeneity of variance, but, usually, they are not examined for normal distribution. In this study I examined the measured items of a carcinogenicity/chronic toxicity study with rats for both homogeneity of variance and normal distribution. It was observed that a lot of hematology and biochemistry items showed non-normal distribution. For testing normal distribution of the data obtained from toxicity studies, the data of the concurrent control group may be examined, and for the data that show a non-normal distribution, non-parametric tests with robustness may be applied.

Phase II trial of cytarabine, cisplatin and vindesine for advanced non-small cell lung cancer.

PubMed

Bianco, A; Perez, J E; Machiavelli, M; Leone, B A; Romero, A; Rabinovich, M G; Vallejo, C T; Rodriguez, R; Cuevas, M A; Alvarez, L A

1990-02-28

Thirty-two patients with advanced non-small cell lung cancer (NSCLC) were entered in this study to evaluate the efficacy and toxicity of a chemotherapy schedule including cisplatin (C) 40 mg/m2 intravenously (i.v.) on days 1-3; vindesine (V) 3 mg/m2 i.v. on day 1, and cytarabine (ara-C) 15 mg/m2 subcutaneously every 12 hours on days 1-3 (total dose: 90 mg/m2). Cisplatin was administered simultaneously with one dose of ara-C. Cycles were repeated every 28 days. Five patients out of 28 (18%) fully evaluable for response presented partial remissions. No complete response was observed. Median survival was 8 months and median duration of response was 4 months. Hematologic toxicity was severe in 3 patients. There were no toxicity-related deaths. Other adverse reactions included nausea and vomiting, alopecia and peripheral neuropathy. We conclude that this chemotherapy combination is marginally effective against NSCLC showing in this group of patients a low number of responses of short duration without a significant impact on survival.

Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia.

PubMed

Gabor, Krisztina Mita; Schermann, Geza; Lautner-Csorba, Orsolya; Rarosi, Ferenc; Erdelyi, Daniel J; Endreffy, Emoke; Berek, Krisztina; Bartyik, Katalin; Bereczki, Csaba; Szalai, Csaba; Semsei, Agnes F

2015-04-01

Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL. We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols. DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively). Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity. © 2015 Wiley Periodicals, Inc.

Toxicity Profile of a Nutraceutical Formulation Derived from Green Mussel Perna viridis

PubMed Central

Joseph, Deepu; Chakkalakal, Selsa J.

2014-01-01

The short-term (acute) and long-term (subchronic) toxicity profile, mean lethal dose 50 (LD50), and no-observed-adverse-effect level (NOAEL) of a nutraceutical formulation developed from green mussel Perna viridis, which showed in vitro and in vivo anti-inflammatory properties, were evaluated in the present study. The formulation was administered to the male and female Wistar rats at graded doses (0.5, 1.0, and 2.5 g/kg body weight) for two weeks of acute toxicity study and 0.5, 1.0, and 2.0 g/kg body weight for 90 days in subchronic toxicity study. The LD50, variations in clinical signs, changes in body weight, body weight, food/water consumption, organ weight (liver, kidney, spleen, and brain), hematology, serum chemistry, and histopathological changes were evaluated. The LD50 of the formulation was 5,000 mg/kg BW. No test article related mortalities as well as change in body weight, and food and water consumption were observed. No toxicity related significant changes were noted in renal/hepatic function, hematological indices, and serum biochemical parameters between the control and treated groups. Histopathological alterations were not observed in the vital organs of rats. The subchronic NOAEL for the formulation in rats is greater than 2000 mg/kg. This study demonstrated that the green mussel formulation is safe to consume without any adverse effects in the body. PMID:24995298

Lecture: fotemustine in brain tumors.

PubMed

Silvani, A; Gaviani, P; Lamperti, E; Botturi, A; Ferrari, D; Simonetti, G; Salmaggi, A

2011-11-01

Fotemustine (FTMS) is a third-generation nitrosourea, in preclinical studies, FTMS compared favorably with carmustine (BCNU) and lomustine (CCNU) against several human tumor cell lines. In conventional schedule, FTMS is administered at a dose of 100 mg/sqm/week for three consecutive weeks as induction (I) treatment, followed by 100 mg/sqm every three weeks, after a 5-week rest, as maintenance (M). Several Italian groups reported the results using FTMS in malignant glioma patients recurring after temozolomide standard treatment. In these papers, the 6-progression free survival are ranging from 20 to 52%. With the schedule (I + M) myelosuppression is observed in more than 30% of patients, and thrombocytopenia and leukopenia are more frequent and significant in Temozolomide pretreated patients. On the bases of the hematological toxicities several authors experimented new schedules of FTMS administrated at low doses. Recently, some authors reported the interesting results of a multicenter study on recurrent glioblastoma multiforme patients combining FTMS with new antiangiogentic agent bevacizumab.

Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro.

PubMed

Torisawa, Yu-suke; Spina, Catherine S; Mammoto, Tadanori; Mammoto, Akiko; Weaver, James C; Tat, Tracy; Collins, James J; Ingber, Donald E

2014-06-01

Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow-on-a-chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro.

Paraoxonase 1 and its relationship with pesticide biomarkers in indigenous Mexican farmworkers.

PubMed

Bernal-Hernández, Yael Yvette; Medina-Díaz, Irma Martha; Barrón-Vivanco, Briscia Socorro; Robledo-Marenco, María de Lourdes; Girón-Pérez, Manuel Iván; Pérez-Herrera, Norma Elena; Quintanilla-Vega, Betzabet; Cerda-Flores, Ricardo; Rojas-García, Aurora Elizabeth

2014-03-01

Biomarkers of pesticide toxicity and paraoxonase 1 (PON1) phenotype and genotypes were evaluated in indigenous Mexican farmworkers exposed mainly to organophosphate (OP) pesticides. Acetylcholinesterase, butyrylcholinesterase, and PON1 activities--arylesterase and CMPAase activities--were evaluated spectrophotometrically. PON1 55 and 192 polymorphisms were determined by real-time polymerase chain reaction. Hematological parameters were evaluated using a cytometer. Butyrylcholinesterase and arylesterase activities were lower in farmworkers, who also showed lower levels of leukocytes but higher percentages of lymphocytes when compared with the nonexposed group. Our results showed a high frequency of OP, high hydrolysis-related PON1 alleles (LL/QR and LL/RR) in the study population. An association was observed between CMPAase activity and PON1Q192R polymorphism. Our results suggest that pesticide exposure modifies biochemical and hematological biomarkers in the study population, and that the phenotype of PON1 (CMPAase) is a sensible susceptibility biomarker of OP pesticide toxicity.

Hematologic changes after total body irradiation and autologous transplantation of hematopoietic peripheral blood progenitor cells in dogs with lymphoma.

PubMed

Escobar, C; Grindem, C; Neel, J A; Suter, S E

2012-03-01

Dogs with and without lymphoma have undergone hematopoietic cell transplantation in a research setting for decades. North Carolina State University is currently treating dogs with B- and T-cell lymphoma in a clinical setting with autologous peripheral blood progenitor cell transplants, using peripheral blood CD34+ progenitor cells harvested using an apheresis machine. Complete blood counts were performed daily for 15 to 19 days posttransplantation to monitor peripheral blood cell nadirs and subsequent CD34+ cell engraftment. This study documents the hematologic toxicities of total body irradiation in 10 dogs and the subsequent recovery of the affected cell lines after peripheral blood progenitor cell transplant, indicating successful CD34+ engraftment. All peripheral blood cell lines, excluding red blood cells, experienced grade 4 toxicities. All dogs had ≥ 500 neutrophils/μl by day 12, while thrombocytopenia persisted for many weeks. All dogs were clinically normal at discharge.

Acute and chronic toxicities of Bacopa monnieri extract in Sprague-Dawley rats.

PubMed

Sireeratawong, Seewaboon; Jaijoy, Kanjana; Khonsung, Parirat; Lertprasertsuk, Nirush; Ingkaninan, Kornkanok

2016-07-27

Bacopa monnieri is a medicinal plant which has long been used in Ayurvedic medicines to augment brain function and to improve memory. The purpose of our study was to identify and evaluate possible toxic effects of B. monnieri extract in rats by assessing hematological, biochemical, and histopathological parameters. Acute oral toxicity of Bacopa monnieri extract was studied in female rats by giving a single orally administered dose at a level of 5,000 mg/kg. The rats were monitored for toxic signs for 14 days. In the chronic toxicity test, groups of both female and male rats were given daily oral doses of B. monnieri extract at dose levels of either 30, 60, 300 or 1,500 mg/kg for 270 days. The behavior and health of the animals was then monitored. At the end of the observation period, the body and organ weights of the rats in each group were measured. Blood was collected and necropsy was performed to evaluate their hematology, blood clinical chemistry, and microanatomy. The acute toxicity test found no significant differences between the experimental and the control group rats. In the chronic toxicity test, animal behavior and health of the experimental groups were normal, just as in the control rats. All values of other parameters assessed remained within the normal range. A single oral administration of B. monnieri extract at the dose of 5,000 mg/kg did not cause any serious undesirable effects. B. monnieri extract at doses of 30, 60, 300 and 1,500 mg/kg given for 270 days did not produce any toxicity in rats.

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer.

PubMed

Abe, Hajime; Mori, Tsuyoshi; Kawai, Yuki; Cho, Hirotomi; Kubota, Yoshihiro; Umeda, Tomoko; Kurumi, Yoshimasa; Tani, Tohru

2013-06-01

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated. Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens--arm A, 3 courses of fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) followed by 3 courses of docetaxel 100 mg/m(2) (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC. Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.

Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies.

PubMed

Abdel-Daim, Mohamed M; Taha, Ramadan; Ghazy, Emad W; El-Sayed, Yasser S

2016-01-01

Diazinon (DZN) is a common organophosphorus insecticide extensively used for agriculture and veterinary purposes. DZN toxicity is not limited to insects; it also induces harmful effects in mammals and birds. Our experiment evaluated the protective and antioxidant potential of sesame oil (SO) and (or) alpha-lipoic acid (ALA) against DZN toxicity in male Wistar albino rats. DZN-treated animals exhibited macrocytic hypochromic anemia and significant increases in serum biochemical parameters related to liver injury, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (γGT), cholesterol, and triglycerides. They also had elevated levels of markers related to cardiac injury, such as lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), and increased biomarkers of renal injury, urea and creatinine. DZN also increased hepatic, renal, and cardiac lipid peroxidation and decreased antioxidant biomarker levels. SO and (or) ALA supplementation ameliorated the deleterious effects of DZN intoxication. Treatment improved hematology and serum parameters, enhanced endogenous antioxidant status, and reduced lipid peroxidation. Importantly, they exerted synergistic hepatoprotective, nephroprotective, and cardioprotective effects. Our findings demonstrate that SO and (or) ALA supplementation can alleviate the toxic effects of DZN via their potent antioxidant and free radical-scavenging activities.

Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vandecasteele, Katrien, E-mail: Katrien.Vandecasteele@uzgent.be; Tummers, Philippe; Makar, Amin

2012-10-01

Purpose: To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). Methods and Materials: Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m Superscript-Two , weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. Results: Regarding acute toxicity (n = 65), Grademore » 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade {>=}2 hematologic toxicity (38% vs. nil, p = 0.003), Grade {>=}2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. Conclusions: Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity.« less

Sub-chronic safety evaluation of aqueous extract of Alangium salvifolium (L.f.) Wangerin leaves in rats

PubMed Central

Kapoor, Bhupinder; Kaur, Gagandeep; Gupta, Mukta; Gupta, Reena

2017-01-01

Conventionally, the juice and extract of Alangium salvifolium leaves have been used for the treatment of diabetes, wound healing, dog bite, and as a poultice in rheumatism. To carry out the sub-chronic toxicity and thereafter safety evaluation of A. salvifolium leaves. The aqueous extract of A. salvifolium leaves was administered orally at the doses of 200, 400, and 800 mg/kg/day for 90 days. All the animals were observed daily for general behavior, changes in body weight, food, and water consumption. At the end of the treatment period, biochemical and hematological parameters were analyzed; and the animals were sacrificed for histopathological examination of heart, lungs, liver, and kidney. The general behavior and water intake were normal in all the rats. The increase in body weight was observed in female rats of all the groups while body weight was decreased in high dose group animals of both sexes. Hematological parameters were not disturbed by the continuous use of extract. A significant decrease in glucose level was observed in intermediate- and high-dose group animals while urea and creatinine level were significantly high in animals of high-dose group. Although histopathological examination of most of the organs exhibited no structural changes, some tubal damage in kidneys was observed in high-dose group animals. The high dose of extract has shown mild signs of toxicity on kidney function test, but no toxic response was observed on hematological and liver biochemical parameters. The extract also exhibited hypoglycemic potential. PMID:28795025

Using [{sup 18}F]Fluorothymidine Imaged With Positron Emission Tomography to Quantify and Reduce Hematologic Toxicity Due to Chemoradiation Therapy for Pelvic Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, Sarah M., E-mail: sarah-mcguire@uiowa.edu; Bhatia, Sudershan K.; Sun, Wenqing

Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [{sup 18}F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity. Methods and Materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose responsemore » of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity. Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test). Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.« less

Evaluation of behavioral parameters, hematological markers, liver and kidney functions in rodents exposed to Deepwater Horizon crude oil and Corexit.

PubMed

Ramesh, Sindhu; Bhattacharya, Dwipayan; Majrashi, Mohammed; Morgan, Marlee; Prabhakar Clement, T; Dhanasekaran, Muralikrishnan

2018-04-15

The 2010 Deepwater Horizon (DWH) oil spill is the largest marine oil spill in US history. In the aftermath of the spill, the response efforts used a chemical dispersant, Corexit, to disperse the oil spill. The health impacts of crude oil and Corexit mixture to humans, mammals, fishes, and birds are mostly unknown. The purpose of this study is to investigate the in vivo effects of DWH oil, Corexit, and oil-Corexit mixture on the general behavior, hematological markers, and liver and kidney functions of rodents. C57 Bl6 mice were treated with DWH oil (80 mg/kg) and/or Corexit (95 mg/kg), and several hematological markers, lipid profile, liver and kidney functions were monitored. The results show that both DWH oil and Corexit altered the white blood cells and platelet counts. Moreover, they also impacted the lipid profile and induced toxic effects on the liver and kidney functions. The impacts were more pronounced when the mice were treated with a mixture of DWH-oil and Corexit. This study provides preliminary data to elucidate the potential toxicological effects of DWH oil, Corexit, and their mixtures on mammalian health. Residues from the DWH spill continue to remain trapped along various Gulf Coast beaches and therefore further studies are needed to fully understand their long-term impacts on coastal ecosystems. Copyright © 2018. Published by Elsevier Inc.

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

PubMed Central

Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

2009-01-01

Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX) : intergroup trial N9741 in first-line treatment of metastatic colorectal cancer.

PubMed

Ashley, Amanda C; Sargent, Daniel J; Alberts, Steven R; Grothey, Axel; Campbell, Megan E; Morton, Roscoe F; Fuchs, Charles S; Ramanathan, Ramesh K; Williamson, Stephen K; Findlay, Brian P; Pitot, Henry C; Goldberg, Richard M

2007-08-01

Efficacy and toxicity of oxaliplatin (Eloxatin; Sanofi-Aventis, Paris, France) combined with irinotecan (IROX) were examined in 383 patients enrolled on the IROX arm of Intergroup Study N9741. This IROX regimen was oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2) administered every 3 weeks. The relation between adverse events on IROX to selected characteristics was analyzed. Time to progression (TTP), response rate, and overall survival for patients treated with IROX compared with patients treated with oxaliplatin with 5- fluorouracil (FOLFOX) were updated in this article. Grade >or=3 gastrointestinal and hematologic toxicities were common with 39% patients experiencing neutropenia, 28% diarrhea, and 21% vomiting. Patients ages >70 years experienced higher rates of grade >or=3 toxicity, with significantly higher rates of grade >or=3 hematologic toxicities (P = .02). Long-term toxicity was uncommon, and nearly all cases of grade >or=3 neurotoxicity resolved within 10 months. Fifty-two percent of patients required dose reductions for adverse events, and 26% experienced 119 hospitalizations related to complications of treatment or their disease, with 5 treatment-related deaths. This analysis confirmed prior findings that FOLFOX is superior to IROX in terms of response rate (43% vs 36%, p = 0.002), TTP (9.2 months vs 6.7 months, P < .0001), and overall survival (19.5 months vs 17.3 months, P = .0001). IROX was found to be less active than FOLFOX but with a similar toxicity profile except in patients ages >70 years. Although IROX may be considered in patients intolerant of 5-FU or in patients known to have a dihydropyrimidine dehydrogenase (DPD) deficiency, it should be used with caution in older patients. (c) 2007 American Cancer Society.

Evaluation of acute and subacute toxicity and mutagenic activity of the aqueous extract of pecan shells [Carya illinoinensis (Wangenh.) K. Koch].

PubMed

Porto, Luiz Carlos Santos; da Silva, Juliana; Ferraz, Alexandre de Barros Falcão; Corrêa, Dione Silva; dos Santos, Marcela Silva; Porto, Caroline Dalla Lana; Picada, Jaqueline Nascimento

2013-09-01

The infusion of pecan shells has been used to prevent and control hypercholesterolemia, diabetes and toxicological diseases. The aim of the present study was to evaluate toxicity and mutagenic effects of pecan shells aqueous extract (PSAE). Wistar rats were treated with a single dose of 300 or 2000 mg/kg of PSAE in the acute toxicity test. For the subacute test, the animals received 10 or 100 mg/kg of PSAE for 28 days. The mutagenicity was evaluated using Salmonella/microsome assay in TA1535, TA1537, TA98, TA100 and TA102 S. typhimurium strains in the presence and absence of metabolic activation (S9 mix) and micronucleus test in bone marrow. HPLC analyses indicated the presence of tannins, flavonoids, gallic and ellagic acids. Except for triglycerides, all treated groups presented normal hematological and biochemical parameters. Lower levels of triglycerides and weight loss were observed in the 100 mg/kg group. Mutagenic activities were not detected in S. typhimurium strains and by the micronucleus test. Based on these results, PSAE was not able to induce chromosomal or point mutations, under the conditions tested. The 100mg/kg dose showed significant antihyperlipidemic action, with no severe toxic effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Blinatumomab: Enlisting serial killer T cells in the war against hematologic malignanciess

PubMed Central

Rogala, Britny; Freyer, Craig W.; Ontiveros, Evelena P.; Griffiths, Elizabeth A.; Wang, Eunice S.; Wetzler, Meir

2016-01-01

Introduction The approval of blinatumomab signals the long awaited arrival of immunotherapy for acute lymphoblastic leukemia (ALL). Previous options for relapsed or refractory disease were restricted to combination cytotoxic chemotherapy with limited efficacy and significant toxicity. Through an innovative mechanism of action, blinatumomab stimulates a polyclonal antitumor T cell response, yielding unprecedented single agent efficacy in the relapsed/refractory setting. Success comes at the cost of immunological toxicities rarely encountered with previous therapies and challenging administration logistics requiring clinical expertise. Areas covered All published clinical and preclinical studies using blinatumomab were reviewed in addition to all registered ongoing clinical trials and data published in abstract form. The search was limited to the English language. The pharmacology, clinical efficacy, toxicity profile, and logistical considerations for drug administration are discussed. Expert Opinion Blinatumomab is an exciting addition to the treatment armamentarium for relapsed/refractory ALL, yet several questions remain regarding optimal implementation into the current treatment paradigm. A unique toxicity profile should be weighed against promising benefits in a poor prognosis population. Other emerging therapies, such as chimeric antigen receptor-modified T cells and inotuzumab ozogamicin, with different side effect profiles and administration schedules, may prove to be more beneficial for specific patient populations. PMID:25985814

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.

PubMed

Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J; Robbins, Paul D; Tchkonia, Tamara; Kirkland, James L

2017-03-08

Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-X L inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

Patient-reported outcomes in drug development for hematology.

PubMed

Acquadro, Catherine; Regnault, Antoine

2015-01-01

Patient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on the patient's perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinical meaningful endpoints to characterize treatment benefit. They provide unique and important information about the effect of treatment from a patient's view. However, PROs will only be considered adequate if the assessment is well-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles to consider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinical trials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, and quality of patient's well-being at short-term and long-term after treatment from a patient's perspective. In situations in which multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to be evaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Given the diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation. The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations. In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials in hematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in the development of new drugs. © 2015 by The American Society of Hematology. All rights reserved.

Frontline strategy for follicular lymphoma: are we ready to abandon chemotherapy?

PubMed

Fowler, Nathan

2016-12-02

Chemotherapy combinations have been the backbone of therapy for follicular lymphoma, and are associated with high initial response rates. Unfortunately, toxicity and secondary malignancies remain concerns, and most advanced-stage patients still relapse within 5 years, regardless of the regimen. Advances in the understanding of lymphoma biology have resulted in a new generation of noncytotoxic therapeutics with significant activity in follicular lymphoma. Recent studies exploring biological and targeted combinations in the frontline have shown promise, with response rates similar to chemotherapy. However, these regimens are also associated with significant cost as well as a unique toxicity profile. Large randomized studies are underway to compare noncytotoxic regimens with chemotherapy in the frontline, and several new combinations are being tested in the phase 2 setting. Ongoing work to identify predictive biomarkers and investment in mechanistic studies will ultimately lead to the personalization of therapy in the frontline setting for follicular lymphoma. © 2016 by The American Society of Hematology. All rights reserved.

Prospective Phase I-II Trial of Helical Tomotherapy With or Without Chemotherapy for Postoperative Cervical Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwarz, Julie K., E-mail: jschwarz@radonc.wustl.edu; Department of Cell Biology and Physiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO

2011-12-01

Purpose: To investigate, in a prospective trial, the acute and chronic toxicity of patients with cervical cancer treated with surgery and postoperative intensity-modulated radiotherapy (RT) delivered using helical tomotherapy, with or without the administration of concurrent chemotherapy. Patients and Methods: A total of 24 evaluable patients entered the study between March 2006 and August 2009. The indications for postoperative RT were tumor size, lymphovascular space invasion, and the depth of cervical stromal invasion in 15 patients; 9 patients underwent postoperative RT because of surgically positive lymph nodes. All patients underwent pelvic RT delivered with helical tomotherapy and intracavitary high-dose-rate brachytherapy.more » Treatment consisted of concurrent weekly platinum in 17, sequential carboplatin/Taxol in 1, and RT alone in 6. The patients were monitored for acute and chronic toxicity using the Common Toxicity Criteria, version 3.0. Results: The median follow-up was 24 months (range, 4-49). At the last follow-up visit, 23 patients were alive and disease free. Of the 24 patients, 12 (50%) experienced acute Grade 3 gastrointestinal toxicity (anorexia in 5, diarrhea in 4, and nausea in 3). One patient developed acute Grade 4 genitourinary toxicity (vesicovaginal fistula). For patients treated with concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 71% and 24%, respectively. For patients treated without concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 29% and 14%, respectively. Two long-term toxicities occurred (vesicovaginal fistula at 25 months and small bowel obstruction at 30 months). The overall and progression-free survival rate at 3 years for all patients was 100% and 89%, respectively. Conclusion: The results of our study have shown that postoperative external RT for cervical cancer delivered with helical tomotherapy and high-dose-rate brachytherapy and with or without chemotherapy is feasible, with acceptable acute and chronic toxicity.« less

Effect of subchronic administration of nutmeg (Myristica fragrans Houtt) ethanolic extract to hematological parameters in rat

NASA Astrophysics Data System (ADS)

Bachri, M. S.; Yuliani, S.; Sari, A. K.

2017-11-01

Nutmeg is dried kernel of broadly ovoid seed of Myristica fragrans Houtt. It has been mentioned in ethnomedical literature as aphrodisiac, stomachic, carminative, tonic, and nervous stimulant. In order to establish the safety of nutmeg, the effect of the repeated administration of nutmeg is needed. The study was aimed to determine the toxic effect of subchronic administration of nutmeg ethanolic extract to hematological parameters in rat. A total of 28 male adult Wistar rats divided into 4 groups. Group I as control was given by 0.5% CMC-suspension, group II, III, and IV were given by 50, 100, and 200 mg/kg bw, respectively, of nutmeg ethanolic extract. The treatments were administered daily for 31 days. On day 31 bloods were taken from orbital sinus. The hematological parameter consisted of the numbers of erythrocyte and leukocyte as well as hemoglobin and total protein levels were measured. The data were statistically analyzed by one way Anova followed by LSD test. All of observed hematological parameters in rats showed that there were no significant difference between the nutmeg ethanolic extract treated groups and control group. The result indicated that the subchronic administration of 50, 100, and 200 mg/kg bw of nutmeg ethanolic extract did not cause the change of hematological parameters in rat.

Leukocyte and platelet changes following low-dose lipopolysaccharide administration in five dogs.

PubMed

Flatland, B; Fry, M M; LeBlanc, C J; Rohrbach, B W

2011-02-01

Effects of low-dose LPS (0.1 μg/kg i.v.) on leukocyte and platelet parameters measured using an Advia 120 hematology analyzer were investigated. Five dogs received a saline sham treatment prior to LPS, and blood was collected before and 3, 6, and 24 h post-treatment. LPS-treated dogs had mild neutrophil toxic change and increased neutrophil bands at 3 and 6 h. Compared to saline-treated controls, total leukocyte, neutrophil, and monocyte counts of LPS-treated dogs were significantly decreased at 3 h and increased at 24 h. Compared to baseline, total leukocyte counts of LPS-treated dogs were significantly decreased at 3 h and increased at 24 h. Mean platelet volume was significantly increased and mean platelet component concentration was decreased at 3 h compared to baseline. Platelet count was significantly decreased at 3 and 6 h; plateletcrit did not change significantly. High dosage is not required in order to detect LPS-mediated hematologic effects in dogs. Low-dose LPS administration causes significant changes in leukocyte and platelet indices in dogs without causing severe clinical signs or death. Copyright © 2010 Elsevier Ltd. All rights reserved.

Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia.

PubMed

Opoka, Robert O; Ndugwa, Christopher M; Latham, Teresa S; Lane, Adam; Hume, Heather A; Kasirye, Phillip; Hodges, James S; Ware, Russell E; John, Chandy C

2017-12-14

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416. © 2017 by The American Society of Hematology.

Brentuximab vedotin in relapsed/refractory Hodgkin’s lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials

PubMed Central

Zinzani, Pier Luigi; Viviani, Simonetta; Anastasia, Antonella; Vitolo, Umberto; Luminari, Stefano; Zaja, Francesco; Corradini, Paolo; Spina, Michele; Brusamolino, Ercole; Gianni, Alessandro M.; Santoro, Armando; Botto, Barbara; Derenzini, Enrico; Pellegrini, Cinzia; Argnani, Lisa

2013-01-01

Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin’s lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10–19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra-hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions. PMID:23645687

Nonprescription analgesics and their use in solid-organ transplantation: a review.

PubMed

Gabardi, Steven; Luu, Linh

2004-09-01

To review the pharmacology, adverse events, drug interactions, and use of the nonprescription analgesics in solid-organ transplant recipients. Studies evaluating nonprescription analgesics in solid-organ transplantation were considered for evaluation. English-language studies were selected for inclusion. Nonprescription analgesics (aspirin, choline salicylate, magnesium salicylate, sodium salicylate, ibuprofen, ketoprofen, naproxen sodium, and acetaminophen) are the most commonly purchased over-the-counter agents in the United States. These agents, although generally considered safe, have been associated with a number of toxicities. The salicylates and nonsteroidal anti-inflammatory drugs have been associated with gastrointestinal damage, hematologic changes, liver and kidney dysfunction, and breathing difficulties. Acetaminophen has been shown to induce hematologic changes and liver and renal dysfunction. A closer look at the nonprescription analgesics reveals their potential for harm when used by solid-organ transplant recipients. In this patient population, the salicylates and nonsteroidal anti-inflammatory drugs should generally be avoided if possible, because of their potential toxicities, especially renal dysfunction. Low-dose aspirin, for the prevention of cardiovascular and cardiocerebral events, appears to be safe, but patients must still be followed closely. Acetaminophen is generally considered the nonprescription analgesic and antipyretic of choice in transplant recipients because of its favorable toxicity profile. However, it is imperative that patients and transplant practitioners are aware that this agent is not without toxicities and proper monitoring is advised.

Hematology and serum chemistry reference ranges of free-ranging moose (Alces alces) in Norway.

PubMed

Rostal, Melinda K; Evans, Alina L; Solberg, Erling J; Arnemo, Jon M

2012-07-01

Baseline reference ranges of serum chemistry and hematology data can be important indicators for the status of both individuals or populations of wild animals that are affected by emerging pathogens, toxicants, or other causes of disease. Frequently, reference ranges for these values are not available for wildlife species or subspecies. We present hematologic and serum chemistry reference ranges for moose (Alces alces) adults, yearlings, and calves in Norway sampled from 1992-2000. Additionally, we demonstrated that both induction time and chase time were correlated with initial rectal temperature, although they were not significantly correlated with cortisol, aspartate aminotransferase, glucose, or creatine kinase. Overall, the reference ranges given here are similar to those given for American moose, with a few differences that can be attributed to environment, testing methodology, or subspecies or species status. This is the first report, to our knowledge, of reference ranges for moose in Norway.

[Influence of trematode invasion and zinc ions on the histometric peculiarities of haemocytes and some hematological indices of Planorbarius purpura (Gastropoda: Pulmonata: Bulinidae)].

PubMed

Kirichuk, G E; Stadnichenko, A P

2010-01-01

Cellular components of the Planorbarius purpura hemolymph are represented by three phyla of haemocytes (prohemocytes, eosinophilis microgranulocytes, and basophilis granulocytes) and vesicular cells. As a result of the invasions of P. purpura with the trematode Echinoparyphium aconiatum, changes of the linear dimensions of granular hemocytes and their nuclei took place. Moreover, an increase of the hemocytes' number per l mm3 of hemolymph and change of the percentages of different hemocyte types were recorded. Under the influence of zinc ions, linear dimensions of prohemocytes and their nuclei (at 10 MPCns of the toxicant) were changed. In granular hemocytes and abnormalities of all histometrical and hematological parameters were observed. All cytometrical, karyometrical, and hematological alterations were expressed more clearly in infested mollusks than in non-infested ones, and occurred usually under lower concentrations of zinc ions.

Evaluating the incidence of leukopenia and neutropenia with valproate, quetiapine, or the combination in children and adolescents.

PubMed

Rahman, Aminur; Mican, Lisa M; Fischer, Charles; Campbell, Angela H

2009-05-01

At the Austin State Hospital, Austin, TX, a number of cases of neutropenia and leukopenia have been observed in children and adolescents who were treated with the combination of valproate and quetiapine. Use of this combination has raised concerns regarding an increased risk of hematologic toxicity. To evaluate the incidence of leukopenia and neutropenia associated with the use of valproate, quetiapine, or the combination in the child and adolescent population. This study was a retrospective evaluation of patients from the child and adolescent psychiatric service of the Austin State Hospital who were treated with valproate, quetiapine, or the combination. Subjects were selected from patients discharged between August 1, 2004, and August 31, 2007. Laboratory data were evaluated to determine the incidence and severity of leukopenia and neutropenia associated with valproate, quetiapine, and a combination of the 2. A total of 131 patients were included in the study. Analysis of the laboratory data revealed a combined incidence of neutropenia and/or leukopenia of 44%, 26%, and 6% in the combination group, valproate monotherapy group, and quetiapine monotherapy group, respectively. Differences in the incidence of neutropenia and/or leukopenia between the quetiapine monotherapy group and valproate monotherapy group, as well as the quetiapine monotherapy group and the combination group reached statistical significance. A significant difference was found among groups based on absolute neutrophil count Common Toxicity Criteria severity (p < 0.001). The combination group differed significantly in incidence of moderate-to-severe neutropenia (14 cases) from both the valproate (5 cases) and quetiapine (0 cases) monotherapy groups. A significantly greater number (44%) of African American patients experienced neutropenia and/or leukopenia than white (not Hispanic or Latino; 29%) or Hispanic or Latino (11%) patients. Patients treated with valproate or the combination of valproate and quetiapine should be monitored for the occurrence of leukopenia and neutropenia. Controlled studies are warranted to examine possible pharmacokinetic and pharmacodynamic interactions with the combination of valproate and quetiapine to further evaluate the hematologic findings of this study.

Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies.

PubMed

Leitch, Heather A; Fibach, Eitan; Rachmilewitz, Eliezer

2017-05-01

Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made. Copyright © 2017 Elsevier B.V. All rights reserved.

In Vivo Human Time-Exposure Study of Orally Dosed Commercial Silver Nanoparticles

PubMed Central

Munger, Mark A.; Radwanski, Przemyslaw; Hadlock, Greg C.; Stoddard, Greg; Shaaban, Akram; Falconer, Jonathan; Grainger, David W.; Deering-Rice, Cassandra E.

2013-01-01

Background Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receives increasing health assessment. Methods We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content was determined. Results No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. Conclusion In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems is warranted to assert human toxicity thresholds. PMID:23811290

Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer.

PubMed

Azadeh, Payam; Mortazavi, Nafiseh; Tahmasebi, Arezoo; Hosseini Kamal, Farnaz; Novin, Kambiz

2016-01-01

The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed. In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens. Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup. © 2015 S. Karger AG, Basel.

Sea buckthorn seed oil protects against the oxidative stress produced by thermally oxidized lipids.

PubMed

Zeb, Alam; Ullah, Sana

2015-11-01

Thermally oxidized vegetable ghee was fed to the rabbits for 14 days with specific doses of sea buckthorn seed oil (SO). The ghee and SO were characterized for quality parameters and fatty acid composition using GC-MS. Rabbits serum lipid profile, hematology and histology were investigated. Major fatty acids were palmitic acid (44%) and oleic acid (46%) in ghee, while SO contains oleic acid (56.4%) and linoleic acid (18.7%). Results showed that oxidized vegetable ghee increases the serum total cholesterol, LDL-cholesterols, triglycerides and decrease the serum glucose. Oxidized ghee produced toxic effects in the liver and hematological parameters. Sea buckthorn oil supplementation significantly lowered the serum LDL-cholesterols, triglycerides and increased serum glucose and body weight of the animals. Sea buckthorn oil was found to reduce the toxic effects and degenerative changes in the liver and thus provides protection against the thermally oxidized lipids induced oxidative stress. Copyright © 2015 Elsevier Ltd. All rights reserved.

Haematolohical profile of subacute oral toxicity of molybdenum and ameliorative efficacy of copper salt in goats.

PubMed

Kusum; Raina, R; Verma, P K; Pankaj, N K; Kant, V; Kumar, J; Srivastava, A K

2010-07-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils.

The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer.

PubMed

Lorusso, Domenica; Fontanella, Caterina; Maltese, Giuseppa; Lepori, Stefano; Tripodi, Elisa; Bogani, Giorgio; Raspagliesi, Francesco

2017-06-01

Recurrence is a common event in endothelial ovarian cancer (EOC) patients, and the choice of the most appropriate treatment is driven by the platinum-free interval, molecular characteristics of the disease such as BRCA mutational status, previous treatments and toxicity. Areas covered: This review focuses on the main hematologic and non-hematologic toxicities correlated with the use of licensed antiangiogenic agents and PARP inhibitors in recurrent platinum-sensitive EOC, providing recommendations for their management. Expert opinion: The clinical research over the next years will be focused on a more precise characterization of molecular pathways underlying tumorigenesis of the five ovarian tumors, to improve the decision-making process in these rare diseases. For this purpose, new study designs and international collaborations will become mandatory. Immunotherapy, antiangiogenic agents and PARP inhibitors will be combined to build a treatment strategy algorithm which will allow patients to receive all the available treatment option, in the more appropriate sequence.

Haematolohical Profile of Subacute Oral Toxicity of Molybdenum and Ameliorative Efficacy of Copper Salt in Goats

PubMed Central

Kusum; Raina, R.; Verma, P. K.; Pankaj, N. K.; Kant, V.; Kumar, J.; Srivastava, A. K.

2010-01-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils. PMID:21170251

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.

PubMed

Moreau, Philippe; Hulin, Cyrille; Macro, Margaret; Caillot, Denis; Chaleteix, Carine; Roussel, Murielle; Garderet, Laurent; Royer, Bruno; Brechignac, Sabine; Tiab, Mourad; Puyade, Mathieu; Escoffre, Martine; Stoppa, Anne-Marie; Facon, Thierry; Pegourie, Brigitte; Chaoui, Driss; Jaccard, Arnaud; Slama, Borhane; Marit, Gerald; Laribi, Karim; Godmer, Pascal; Luycx, Odile; Eisenmann, Jean-Claude; Allangba, Olivier; Dib, Mamoun; Araujo, Carla; Fontan, Jean; Belhadj, Karim; Wetterwald, Marc; Dorvaux, Véronique; Fermand, Jean-Paul; Rodon, Philippe; Kolb, Brigitte; Glaisner, Sylvie; Malfuson, Jean-Valere; Lenain, Pascal; Biron, Laetitia; Planche, Lucie; Caillon, Helene; Avet-Loiseau, Herve; Dejoie, Thomas; Attal, Michel

2016-05-26

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27. © 2016 by The American Society of Hematology.

Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C

PubMed Central

Lens, Sabela; Calleja, Jose L; Campillo, Ana; Carrión, Jose A; Broquetas, Teresa; Perello, Christie; de la Revilla, Juan; Mariño, Zoe; Londoño, María-Carlota; Sánchez-Tapias, Jose M; Urbano-Ispizua, Álvaro; Forns, Xavier

2015-01-01

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications. PMID:25954117

HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer

PubMed Central

Garziera, Marica; Virdone, Saverio; De Mattia, Elena; Scarabel, Lucia; Cecchin, Erika; Polesel, Jerry; D’Andrea, Mario; Pella, Nicoletta; Buonadonna, Angela; Favaretto, Adolfo; Toffoli, Giuseppe

2017-01-01

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. PMID:28653974

Development of CAR T cells designed to improve antitumor efficacy and safety

PubMed Central

Jaspers, Janneke E.; Brentjens, Renier J.

2017-01-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are ‘on-target, off-tumor’ toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. PMID:28342824

Development of CAR T cells designed to improve antitumor efficacy and safety.

PubMed

Jaspers, Janneke E; Brentjens, Renier J

2017-10-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. Published by Elsevier Inc.

THERAPY OF POLYCYTHEMIA VERA WITH RADIOYTTRIUM (Y-90)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greenburg, J.; Sawitsky, A.; Dudley, H.C.

1962-01-01

BS>Nine patients with polycythemia vera were treated from 5-l7 months ago with a single intravenous injection of chelated radioactive yttrium (Y-90) in dosages ranging from 0.l0 to 0.25 mc/kg of body weight. An excellent response, both clinical and hematologic, was obtained in all the patients. This includes relief of symptoms, regression of organomegaly, and normalization of the hematologic picture. Two of these patients, treated l6 and 9 months ago, may possibly be going into relapse. The others are continuing in essentially complete remission. Toxicity was limtted to transient petechiosis and epistaxis, from which recovery was spontaneous. (auth)

[Induction chemotherapy with docetaxel plus cisplatin (TP regimen) followed by concurrent chemoradiotherapy with TP regimen versus cisplatin in treating locally advanced nasopharyngeal carcinoma].

PubMed

Xie, Fang-Yun; Zou, Guo-Rong; Hu, Wei-Han; Qi, Shu-Nan; Peng, Miao; Li, Ji-Shi

2009-03-01

Clinical trials on docetaxel plus cisplatin (DDP) (TP regimen) in treating nasopharyngeal carcinoma (NPC) are still uncertain due to limited samples. This study was to compare the short-term efficacy and toxicity of induction chemotherapy with TP regimen followed by concurrent chemoradiotherapy with TP regimen versus DDP in treating locally advanced NPC. Fifty-seven patients with stage T3-4N2-3M0 NPC diagnosed pathologically from December 2005 to December 2006 were randomized into TP group (30 patients) and DDP group (27 patients). Both groups received TP regimen as induction chemotherapy with docetaxel (70 mg/m(2)) on Day 1 and DDP (80 mg/m(2)) on Day 2, repeating every 21 days for 2 cycles. For concurrent chemotherapy, TP group were administered docetaxel (60 mg/m(2)) on Day 1 and DDP (80 mg/m(2)) on Day 2; DDP group were administered DDP (80 mg/m(2)) on Day 1. Both schedules were repeated every 21 days for 2 cycles. Linear accelerator was used as radioactive source. Irradiation field was designed with CT-simulation and conventional fractions. The 57 patients received 111 cycles of induction chemotherapy, and 53 of them received 103 cycles of concurrent chemotherapy; four patients ceased induction chemotherapy and three ceased concurrent chemotherapy. All patients completed radiotherapy. The major toxicity of induction chemotherapy was hematologic toxicity; the main toxicities of concurrent chemoradiotherapy were hematologic toxicity and mucositis. The occurrence rates of Grade 3-4 leucopenia and Grade 3-4 neutropenia were significantly higher in TP group than in DDP groups (p <0.05). In concurrent chemoradiotherapy, the application rate of granulocyte colony stimulating factor (G-CSF) was significantly higher in TP group than in DDP group (100% vs. 72.0%, p<0.05). After concurrent chemoradiotherapy, the complete remission (CR) rates of the nasopharynx and regional lymph nodes were 93.3% and 92.9% in TP group, and were 96.3% and 91.3% in DDP group (p>0.05). The short-term efficacy of induction chemotherapy with TP regimen followed by concurrent chemoradiotherapy with TP regimen on locally advanced NPC is similar to that of TP regimen followed by concurrent chemoradiotherapy with DDP. The toxicity of the former schedule is severer than that of the latter, but it is tolerable with the use of G-CSF. The long-term efficacy of induction chemotherapy with TP regimen followed by concurrent chemoradiotherapy with TP regimen need to be further studied.

Acute toxic effects of single dose dacarbazine: hematological and histological changes in an animal model.

PubMed

Milijašević, B; Stefanović, D; Lalić-Popović, M; Tomić, Z; Kolarović, J; Lalošević, D; Mikov, M

2014-11-01

Treatment of advanced soft tissue sarcoma usually includes dacarbazine (DTIC), an alkylating agent that methylates DNA and is active during all phases of the cell cycle. Common side effects of DTIC include nausea, vomiting, impaired liver and kidney function, myelosuppression, and pneumonia. There are no accounts, however, of histological and hematological changes caused by DTIC. We investigated acute hematological and morphological changes in different organs and in tumors that were caused by a single dose of DTIC. Adult Syrian golden hamsters were inoculated with a suspension of tumorigenic baby hamster kidney (BHK) cells by subcutaneous injection. On day 14 after inoculation, doses of 1.4, 1.6, 1.8 or 2.0 g/m(2) DTIC were injected intraperitoneally into the hamsters. Hamsters in the control group were injected with physiological saline in the same way. Seven days after drug or saline injection the animals were sacrificed and samples of blood, heart, kidney, liver, lungs, spleen, small intestine and tumor were excised, processed and analyzed. Mitoses were counted using an ocular extension with engraved frame. Anemia, thrombocytopenia and leukocytosis were found in the control group of hamsters with fibrosarcoma, whereas animals with fibrosarcoma treated with DTIC developed anemia, thrombocytopenia and leukopenia. Severe pneumonia and moderate hepatitis were detected in all DTIC treated groups. Effects of DTIC on tumor cells included rounding and enlargement of nuclei and rarefaction of chromatin. The number of mitoses was reduced with increasing doses of DTIC. Hepatitis, myelosuppression, pneumonia, and dose-related inhibition of tumor cell proliferation were observed after a single dose of DTIC.

Hematopoietic Cell Transplantation Using Reduced-Intensity Conditioning Is Successful in Children with Hematologic Cytopenias of Genetic Origin.

PubMed

Kothari, Alok; Ngwube, Alexander; Hayashi, Robert; Murray, Lisa; Davis, Jeffrey; Haut, Paul; Loechelt, Brett J; Shenoy, Shalini

2015-07-01

Genetically derived hematologic cytopenias are a rare heterogeneous group of disorders. Allogeneic hematopoietic cell transplantation (HCT) is curative but offset by organ toxicities from the preparative regimen, graft rejection, graft-versus-host disease (GVHD), or mortality. Because of these possibilities, consideration of HCT can be delayed, especially in the unrelated donor setting. We report a prospective multicenter trial of reduced-intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan and HCT in 11 children with marrow failure of genetic origin (excluding Fanconi anemia) using the best available donor source (82% from unrelated donors). The median age at transplantation was 23 months (range, 2 months to 14 years). The median times to neutrophil (>500 × 10(6)/L) and platelet (>50 × 10(9)/L) engraftment were 13 (range, 12 to 24) and 30 (range, 7 to 55) days, respectively. The day +100 probability of grade II to IV acute GVHD and the 1-year probability of limited and extensive GVHD were 9% and 27%, respectively. The probability of 5-year overall and event-free survival was 82%; 9 patients were alive with normal blood counts at last follow-up and all were successfully off systemic immunosuppression. In patients with genetically derived severe hematologic cytopenias, allogeneic HCT with this RIC regimen was successful in achieving a cure. This experience supports consideration of HCT early in such patients even in the absence of suitable related donors. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The effect of lead poisoning on hematologic and biochemical values in trumpeter swans and Canada geese.

PubMed

Katavolos, P; Staempfli, S; Sears, W; Gancz, A Y; Smith, D A; Bienzle, D

2007-12-01

Lead is a persistent contaminant in the environment, and waterfowl are susceptible to lead toxicity from ingestion of lead pellets and fishing weights. Lead affects numerous physiologic processes through inhibition of enzyme activity and protein function, but its effects on commonly assessed avian blood values are incompletely understood. Our aim was to evaluate hematologic and biochemical changes associated with blood lead concentrations in trumpeter swans and Canada geese. Data for CBCs, plasma biochemical profiles (total protein, albumin, glucose, cholesterol, total bilirubin, calcium, phosphorus, gamma-glutamyltransferase [GGT], aspartate aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, creatine kinase, amylase, and lipase), and whole blood lead concentrations were retrospectively analyzed for 69 trumpeter swans and 52 Canada geese. Laboratory data obtained prospectively from an additional 20 trumpeter swans also were included. RBC morphology was semiquantitated in blood smears from 70 of the birds. Data were analyzed initially by ANOVA and covariance. A statistical model then was constructed to determine the relationship between each parameter and lead concentration. In both avian species, PCV, hemoglobin concentration, and MCHC decreased significantly (P < .05) with increasing blood lead concentration. Uric acid concentration and GGT activity were increased in trumpeter swans and phosphorus concentration was decreased in Canada geese in association with high blood lead concentration (P < .05). Lead toxicosis induced significant changes in the values of commonly measured hematologic parameters in waterfowl. These changes may be useful indicators of severe lead intoxication during routine laboratory assessment. Changes in clinical chemistry values, although statistically significant, were too inconsistent to serve as indicators of lead toxicosis.

CONSEQUENCES OF ACUTE AND CHRONIC EXPOSURE TO ARSENIC

EPA Science Inventory

Arsenic is a toxic chemical and may cause adverse health effects in children and adults. It is known to affect the nervous, gastrointestinal, and hematological systems and cause skin and internal cancers in people exposed to levels greater than 300 ppb in their drinking water. Fo...

Verification and quality control of routine hematology analyzers.

PubMed

Vis, J Y; Huisman, A

2016-05-01

Verification of hematology analyzers (automated blood cell counters) is mandatory before new hematology analyzers may be used in routine clinical care. The verification process consists of several items which comprise among others: precision, accuracy, comparability, carryover, background and linearity throughout the expected range of results. Yet, which standard should be met or which verification limit be used is at the discretion of the laboratory specialist. This paper offers practical guidance on verification and quality control of automated hematology analyzers and provides an expert opinion on the performance standard that should be met by the contemporary generation of hematology analyzers. Therefore (i) the state-of-the-art performance of hematology analyzers for complete blood count parameters is summarized, (ii) considerations, challenges, and pitfalls concerning the development of a verification plan are discussed, (iii) guidance is given regarding the establishment of reference intervals, and (iv) different methods on quality control of hematology analyzers are reviewed. © 2016 John Wiley & Sons Ltd.

[Are non-clinical studies predictive of adverse events in humans?].

PubMed

Claude, N

2007-09-01

The predictibility of adverse events induced by drugs in non-clinical safety studies performed on in vitro and/or in vivo models is a key point for the safety of humans exposed to pharmaceuticals. The strength and the weakness of animal studies to predict human toxicity were assessed by an international study on the concordance of the toxicity of 150 pharmaceuticals observed in humans with that observed in experimental animals. The results showed a good correlation (70% of the adverse events in humans were detected in animal studies) and an early time to first appearance of concordant animal toxicity: 94% were first observed in studies of 1 month or less in duration. The highest incidence of overall concordance was seen in hematological and cardiovascular adverse effects and the least was seen in cutaneous and ophthalmological adverse effects. These studies, scientifically and regulatory standardized, need, in some cases to be adapted to specific problems linked to sensitive populations (young, old or with a pathology which could be worsened by the drug), or specific pharmaceuticals (produced by biotechnology). Some severe adverse events are not detected in conventional animal models (immuno-allergy, idiosyncrasy). Taken together, these elements support the value of toxicology studies to predict many human toxic events associated with pharmaceuticals. Nevertheless, a part of human toxicity is not detected by these experimental approaches, and new tools developed through progress in biology and bio-informatics should reduce this uncertainly margin.

Evaluation of processed borax as antidote for aconite poisoning.

PubMed

Sarkar, Prasanta Kumar; Prajapati, Pradeep K; Shukla, Vinay J; Ravishankar, Basavaiah

2017-06-09

Aconite root is very poisonous; causes cardiac arrhythmias, ventricular fibrillation and ventricular tachycardia. There is no specific antidote for aconite poisoning. In Ayurveda, dehydrated borax is mentioned for management of aconite poisoning. The investigation evaluated antidotal effect of processed borax against acute and sub-acute toxicity, cardiac toxicity and neuro-muscular toxicity caused by raw aconite. For acute protection Study, single dose of toxicant (35mg/kg) and test drug (22.5mg/kg and 112.5mg/kg) was administered orally, and then 24h survival of animals was observed. The schedule was continued for 30 days in sub-acute protection Study with daily doses of toxicant (6.25mg/kg), test drug (22.5mg/kg and 112.5mg/kg) and vehicle. Hematological and biochemical tests of blood and serum, histopathology of vital organs were carried out. The cardiac activity Study was continued for 30 days with daily doses of toxicant (6.25mg/kg), test drug (22.5mg/kg), processed borax solution (22.5mg/kg) and vehicle; ECG was taken after 1h of drug administration on 1 TB , 15th and on 30th day. For neuro-muscular activity Study, the leech dorsal muscle response to 2.5µg of acetylcholine followed by response of toxicant at 25µg and 50µg doses and then response of test drug at 25µg dose were recorded. Protection index indicates that treated borax gave protection to 50% rats exposed to the lethal dose of toxicant in acute protection Study. Most of the changes in hematological, biochemical parameters and histopathological Study induced by the toxicant in sub-acute protection Study were reversed significantly by the test drug treatment. The ventricular premature beat and ventricular tachyarrhythmia caused by the toxicant were reversed by the test drug indicate reversal of toxicant induced cardio-toxicity. The acetylcholine induced contractions in leech muscle were inhibited by toxicant and it was reversed by test drug treatment. The processed borax solution is found as an effective protective agent to acute and sub-acute aconite poisoning, and aconite induced cardiac and neuro-muscular toxicity. Processed borax at therapeutic dose (22.5mg/kg) has shown better antidotal activity profile than five times more than therapeutic dose (112.5mg/kg). Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

[Subchronic toxicity testing of mold-ripened cheese].

PubMed

Schoch, U; Lüthy, J; Schlatter, C

1984-08-01

The biological effects of known mycotoxins of Penicillium roqueforti or P. camemberti and other still unknown, but potentially toxic metabolites in mould ripened cheese (commercial samples of Blue- and Camembert cheese) were investigated. High amounts of mycelium (equivalents of 100 kg cheese/man and day) were fed to mice in a subchronic feeding trial. The following parameters were determined: development of body weight, organ weights, hematology, blood plasma enzymes. No signs of adverse effects produced by cheese mycotoxins could be detected after 28 days. No still unknown toxic metabolites could be demonstrated. From these results no health hazard from the consumption of mould ripened cheese, even in high amounts, appears to exist.

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Fourteen-Day Subchronic Oral Toxicity Study of Nitroguanidine in Rats

DTIC Science & Technology

1988-06-01

Beckett , SGT Samuel S. Liu, BS, and SP4 Gary E. Mattison provided hematology support; SP4 Julius Harmon and Mary E. Lyons provided clinical...Count xlO6/^! xl03/|il White Blnod Cell Differential Neutro- Lympho- Eosino- Mono- phils cytes phils cytes % % % % 0 85D00308

Endothelial Cell-Specific Molecule-1 in Critically Ill Patients With Hematologic Malignancy.

PubMed

Zafrani, Lara; Resche-Rigon, Matthieu; De Freitas Caires, Nathalie; Gaudet, Alexandre; Mathieu, Daniel; Parmentier-Decrucq, Erika; Lemiale, Virginie; Mokart, Djamel; Pène, Frédéric; Kouatchet, Achille; Mayaux, Julien; Vincent, François; N'yunga, Martine; Bruneel, Fabrice; Rabbat, Antoine; Lebert, Christine; Perez, Pierre; Meert, Anne-Pascale; Benoit, Dominique; Darmon, Michael; Azoulay, Elie

2018-03-01

To assess whether serum concentration of endothelial cell-specific molecule-1 (Endocan) at ICU admission is associated with the use of ICU resources and outcomes in critically ill hematology patients. Prospective multicenter cohort study. Seventeen ICUs in France and Belgium. Seven hundred forty-four consecutive critically ill hematology patients; 72 critically ill septic patients without hematologic malignancy; 276 healthy subjects. None. Median total endocan concentrations were 4.46 (2.7-7.8) ng/mL. Endocan concentrations were higher in patients who had received chemotherapy before ICU admission (4.7 [2.8-8.1] ng/mL vs. 3.7 [2.5-6.3] ng/mL [p = 0.002]). In patients with acute respiratory failure, endocan levels were increased in patients with drug-induced pulmonary toxicity compared with other etiologies (p = 0.038). Total endocan levels higher than 4.46 ng/mL were associated with a higher cumulative probability of renal replacement therapy requirement (p = 0.006), a higher requirement of mechanical ventilation (p = 0.01) and a higher requirement of vasopressors throughout ICU stay (p < 0.0001). By multivariate analysis, total endocan levels at admission were independently associated with ICU mortality (odds ratios, 1.39; 95% CI, 1.06-1.83; p = 0.018). The predictive value of endocan peptide fragments of 14 kDa in terms of mortality and life-sustaining therapies requirement was inferior to that of total endocan. Endocan levels were higher in critically ill hematology patients compared with healthy subjects (p < 0.0001) but lower than endocan values in critically ill septic patients without hematologic malignancy (p = 0.005) CONCLUSIONS:: Serum concentrations of endocan at admission are associated with the use of ICU resources and mortality in critically ill hematology patients. Studies to risk-stratify patients in the emergency department or in the hematology wards based on endocan concentrations to identify those likely to benefit from early ICU management are warranted.

In vivo toxicity evaluation of aqueous acetone extract of Terminalia bellirica (Gaertn.) Roxb. fruit.

PubMed

Jayesh, Kuriakose; Helen, Lal Raisa; Vysakh, A; Binil, Eldhose; Latha, M S

2017-06-01

Terminalia bellirica (Gaertn.) Roxb. (Family: Combretaceae), known as Bhibhitaki in Sanskrit and locally known as Behera in India is one of the oldest medicinal plants which has widely been used in the traditional system of medicine, especially in Ayurveda for centuries. The dried fruit of Terminalia bellirica is used for treating various ailments. Aqueous acetone extract of Terminalia bellirica (Gaertn.) Roxb fruits (AATB), showed antioxidant potential in our screening study is selected for the present in vivo toxicity evaluation. Acute administration of AATB was done in female Wistar Albino rats as a single dose up to 2000 mg/kg body weight. At the end of the study, Blood was collected for biochemical and hematological analyses, while histological examinations were performed on liver and kidney. There was no alteration in the behavioral pattern, food and water intake in the treated animals. The relative organ weight, biochemical parameters, hematological parameters and histopathological analysis were also found normal. All the parameters of the toxicity evaluation were found to be normal and the data suggests aqueous acetone extract of Terminalia bellirica fruit is safe, to be used as a traditional herbal formulation for its antioxidant potential and other health benefits. Copyright © 2017 Elsevier Inc. All rights reserved.

Canadian supportive care recommendations for the management of neutropenia in patients with cancer.

PubMed

Kouroukis, C T; Chia, S; Verma, S; Robson, D; Desbiens, C; Cripps, C; Mikhael, J

2008-01-01

Hematologic toxicities of cancer chemotherapy are common and often limit the ability to provide treatment in a timely and dose-intensive manner. These limitations may be of utmost importance in the adjuvant and curative intent settings. Hematologic toxicities may result in febrile neutropenia, infections, fatigue, and bleeding, all of which may lead to additional complications and prolonged hospitalization. The older cancer patient and patients with significant comorbidities may be at highest risk of neutropenic complications. Colony-stimulating factors (csfs) such as filgrastim and pegfilgrastim can effectively attenuate most of the neutropenic consequences of chemotherapy, improve the ability to continue chemotherapy on the planned schedule, and minimize the risk of febrile neutropenia and infectious morbidity and mortality. The present consensus statement reviews the use of csfs in the management of neutropenia in patients with cancer and sets out specific recommendations based on published international guidelines tailored to the specifics of the Canadian practice landscape. We review existing international guidelines, the indications for primary and secondary prophylaxis, the importance of maintaining dose intensity, and the use of csfs in leukemia, stem-cell transplantation, and radiotherapy. Specific disease-related recommendations are provided related to breast cancer, non-Hodgkin lymphoma, lung cancer, and gastrointestinal cancer. Finally, csf dosing and schedules, duration of therapy, and associated acute and potential chronic toxicities are examined.

[Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats].

PubMed

Ogawa, Yukio; Sekita, Kiyoshi; Umemura, Takashi; Saito, Minoru; Ono, Atsushi; Kawasaki, Yasushi; Uchida, Osayuki; Matsushima, Yuko; Inoue, Tohru; Kanno, Jun

2004-02-01

A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.

Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase.

PubMed

Del Re, Marzia; Restante, Giuliana; Di Paolo, Antonello; Crucitta, Stefania; Rofi, Eleonora; Danesi, Romano

2017-01-01

Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Enzymes involved in this pathway include dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and its prodrugs. Candidate gene approaches have demonstrated associations between 5-FU treatment outcomes and germline polymorphisms in DPD. The aim of this review is to report and discuss the latest results on fluoropyrimidine pharmacogenetics. Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such DPD, DPYD, fluoropyrimdines, polymorphisms, toxicity, pharmacogenetics. To date, many sequence variations have been identified within DPYD gene, although the majority of these have no functional consequences on enzymatic activity. Nowadays, there is a general agreement on the clinical significance of the importance of DPD deficiency in patients who suffer from severe, life-threatening drug toxicity although preemptive testing is not applied to all patients. Considering the published literature, clinicians are strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patients candidate to a fluoropyrimidine-based regimens, in order to prevent toxicities and personalise treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies.

PubMed Central

Bucher, J R; Gupta, B N; Adkins, B; Thompson, M; Jameson, C W; Thigpen, J E; Schwetz, B A

1987-01-01

Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. During exposures, signs of restlessness, lacrimation, and a reddish discharge from the nose and mouth were evident in rats and mice. Following exposures, rats and mice were dyspneic and weak. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. No significant clinical pathology, or hematologic changes were observed in exposed rats. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3622444

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

PubMed Central

Tshilolo, Léon; Santos, Brigida; Tomlinson, George A.; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K.; Olupot‐Olupot, Peter; Williams, Thomas N.; Odame, Isaac; Ware, Russell E.

2015-01-01

Background Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers. Procedure A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. Conclusions REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. PMID:26275071

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.

PubMed

McGann, Patrick T; Tshilolo, Léon; Santos, Brigida; Tomlinson, George A; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K; Olupot-Olupot, Peter; Williams, Thomas N; Odame, Isaac; Ware, Russell E

2016-01-01

Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers. A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of four different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. © 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

Acute toxicity assessment of choline by inhalation, intraperitoneal and oral routes in Balb/c mice.

PubMed

Mehta, Amit Kumar; Arora, Naveen; Gaur, Shailendra Nath; Singh, Bhanu Pratap

2009-08-01

Studies suggest that choline has potential to be used as a dietary supplement and a drug for immune inflammatory diseases like asthma and rhinitis. But there are apprehensions regarding adverse effects of choline when given orally in high doses. To address this knowledge gap, toxicity assessment of choline chloride was carried out by intranasal (i.n.), oral and intraperitoneal (i.p.) routes in Balb/c mice for 28days. Body weight, food and water consumption of mice were recorded daily. Hematology and clinical chemistry were assessed to check hepatocellular functions and morphological alterations of the cells. Splenocyte counts were analysed for evaluating cellular immunity. Liver function test was performed by assaying different enzyme systems in serum such as, urea, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Body weight, food and water consumption did not differ between mice treated with choline and the saline control group. Hematologic and biochemical variables were not affected with any increase in serum toxicity marker enzymes indicating normal liver functioning. Choline administration did not affect total cholesterol and high density lipoprotein levels as compared to their respective controls. Urea and blood urea nitrogen levels in choline treated mice were not different than controls. Creatinine level was, however, higher than control in i.p. treatment group, but other parameters were normal. In conclusion, the repeated consumption of choline chloride via i.n. and oral or i.p. routes did not cause toxicity in mice in the toxicological endpoints examined.

Effect of Pachybasin on General Toxicity and Developmental Toxicity in Vivo.

PubMed

Lin, Yi-Ruu; Peng, Kou-Cheng; Chan, Ming-Huan; Peng, Huan-Lin; Liu, Shu-Ying

2017-12-06

To document the safety of pachybasin, a secondary metabolite of Trichoderma harzianum, for use as a bioagricultural agent, it was subjected to general toxicological testing in mice and developmental toxicity in zebrafish. With either 5 or 20 mg kg -1 pachybasin i.p. injection, mice behavioral responses such as motor coordination, spontaneous locomotor activity, or nociceptive pain were not influenced. In long-term effect (daily injection for 14 days), the physiological, hematological, liver, and kidney functions were not altered either. Evidence for the developmental toxicity of pachybasin (10-100 μM) in 72-h exposure period was shown in zebrafish larvae, based on developmental retardation, impairment of chorion, and increase of mortality. In summary, there are no significant general toxicities presented in the pachybasin-treated adult male mice. However, the embryo-toxicity in aquatic biota should be taken into consideration during bioagricultural agent application.

The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy.

PubMed

Eipel, O T; Németh, K; Török, D; Csordás, K; Hegyi, M; Ponyi, A; Ferenczy, A; Erdélyi, D J; Csóka, M; Kovács, G T

2013-02-01

The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.

Conventional radiotherapy with concurrent weekly Cisplatin in locally advanced head and neck cancers of squamous cell origin - a single institution experience.

PubMed

Dimri, Kislay; Pandey, Awadhesh Kumar; Trehan, Romeeta; Rai, Bhavana; Kumar, Anup

2013-01-01

Platinum based concurrent chemo-radiation is the de-facto standard of care in the non-surgical management of locally-advanced head and neck cancer of squamous origin. Three-weekly single agent cisplatin at 100 mg/m2 concurrent with radical radiotherapy has demonstrated consistent improvement in loco-regional control and survival. This improvement is however at the cost of considerable hematologic toxicity and poor overall compliance. The routine use of this regime is improbable in developing countries with limited resources. We therefore aimed to determine the safety and efficacy of an alternative regime of weekly cisplatin and concurrent radiotherapy in such patients. January-05 and April-12, 188 patients of locally-advanced head and neck cancer of squamous origin were treated with concurrent weekly-cisplatin at 35 mg/m2 and conventional radiotherapy 60-66Gy/30-33 fractions/5 days per week. Overall, 95% patients received planned doses of RT while 74% completed within the stipulated overall treatment time of <50 days. Eighty-two percent received at-least 5 weekly cycles. Grade-III/IV mucositis was seen in 58%/9% respectively, which resulted in mean weight loss of 9.2% from a pre-treatment mean of 54.5 kg. Grade-III hematologic toxicity-0.5%; grade II nephrotoxicity-2.5% and grade III emesis-3% were also seen. Grade-III/IV subcutaneous toxicity-10%/1% and grade-III/IV xerostomia-10%/0% were observed. Complete responses at the primary site, regional nodes and overall disease were seen in 86%, 89% and 83% patients respectively. The median and 5-years disease-free survival were 26 months and 39.4% respectively, while the median and overall survival were 27 months and 41.8% respectively. Weekly-cisplatin at 35 mg /m2 when delivered concurrently with conventional radical RT (at-least 66y/33 fractions) in locally-advanced head and neck cancer is well tolerated with minimal hematologic and neprologic toxicity and can be routinely delivered on an out-patient basis. It is an effective alternative to the standard 3-weekly cisplatin especially in the context of developing countries.

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats

PubMed Central

Han, Chung-Tack; Kim, Myoung-Jun; Moon, Seol-Hee; Jeon, Yu-Rim; Hwang, Jae-Sik; Nam, Chunja; Park, Chong-Woo; Lee, Sun-Ho; Na, Jae-Bum; Park, Chan-Sung; Park, Hee-Won; Lee, Jung-Min; Jang, Ho-Song; Park, Sun-Hee; Han, Kyoung-Goo; Choi, Young Whan

2015-01-01

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes. PMID:26877842

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats.

PubMed

Han, Chung-Tack; Kim, Myoung-Jun; Moon, Seol-Hee; Jeon, Yu-Rim; Hwang, Jae-Sik; Nam, Chunja; Park, Chong-Woo; Lee, Sun-Ho; Na, Jae-Bum; Park, Chan-Sung; Park, Hee-Won; Lee, Jung-Min; Jang, Ho-Song; Park, Sun-Hee; Han, Kyoung-Goo; Choi, Young Whan; Lee, Hye-Yeong; Kang, Jong-Koo

2015-12-01

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes.

Increased Risk of Severe Infant Anemia Following Exposure to Maternal HAART, Botswana

PubMed Central

Dryden-Peterson, Scott; Shapiro, Roger L.; Hughes, Michael D.; Powis, Kathleen; Ogwu, Anthony; Moffat, Claire; Moyo, Sikhulile; Makhema, Joseph; Essex, Max; Lockman, Shahin

2011-01-01

Background Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission (MTCT), but may increase the risk for infant anemia. Methods The incidence of first severe anemia (Grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana MTCT prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). Results A total of 1719 infants were analyzed— 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P<0.001) and 2.5% of ZDV-FF infants (P<0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Conclusions Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study. Trial Registration ClinicalTrials.gov identifiers: NCT00197587 and NCT00270296. PMID:21266910

Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers.

PubMed

Villard, Linda; Romer, Anna; Marincek, Nicolas; Brunner, Philippe; Koller, Michael T; Schindler, Christian; Ng, Quinn K T; Mäcke, Helmut R; Müller-Brand, Jan; Rochlitz, Christoph; Briel, Matthias; Walter, Martin A

2012-04-01

Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes. In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) or with cycles alternating between [(90)Y-DOTA]-TOC and (177)lutetium-labeled DOTA-TOC ([(177)Lu-DOTA]-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles. A total of 486 patients completed three or more treatment cycles; 237 patients received [(90)Y-DOTA]-TOC and 249 patients received [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC. Patients receiving [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC had a significantly longer survival than patients receiving [(90)Y-DOTA]-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups. [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC was associated with improved overall survival compared with [(90)Y-DOTA]-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.

Mequindox Induced Genotoxicity and Carcinogenicity in Mice

PubMed Central

Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice. PMID:29692735

Mequindox Induced Genotoxicity and Carcinogenicity in Mice.

PubMed

Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N -oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo , and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.

PubMed

Nahas, Myrna R; Rosenblatt, Jacalyn; Lazarus, Hillard M; Avigan, David

2018-02-15

The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Radiotherapy concurrently with weekly cisplatin, followed by adjuvant chemotherapy, for N2–3 nasopharyngeal cancer: a multicenter trial of the Forum for Nuclear Cooperation in Asia

PubMed Central

Ohno, Tatsuya; Thinh, Dang Huy Quoc; Kato, Shingo; Devi, C.R. Beena; Tung, Ngo Thanh; Thephamongkhol, Kullathorn; Calaguas, Miriam Joy C.; Zhou, Juying; Chansilpa, Yaowalak; Supriana, Nana; Erawati, Dyah; Banu, Parvin Akhter; Koo, Cho Chul; Kobayashi, Kunihiko; Nakano, Takashi; Tsujii, Hirohiko

2013-01-01

The purpose of this study was to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly cisplatin, followed by adjuvant chemotherapy, for the treatment of N2–3 nasopharyngeal cancer (NPC) in Asian countries, especially regions of South and Southeast Asian countries where NPC is endemic. Between 2005 and 2009, 121 patients with NPC (T1–4 N2–3 M0) were registered from Vietnam, Malaysia, Indonesia, Thailand, The Philippines, China and Bangladesh. Patients were treated with 2D radiotherapy concurrently with weekly cisplatin (30 mg/m 2), followed by adjuvant chemotherapy, consisting of cisplatin (80 mg/m2 on Day 1) and fluorouracil (800 mg/m2 on Days 1–5) for 3 cycles. Of the 121 patients, 56 patients (46%) required interruption of RT. The reasons for interruption of RT were acute non-hematological toxicities such as mucositis, pain and dermatitis in 35 patients, hematological toxicities in 11 patients, machine break-down in 3 patients, poor general condition in 2 patients, and others in 8 patients. Of the patients, 93% completed at least 4 cycles of weekly cisplatin during radiotherapy, and 82% completed at least 2 cycles of adjuvant chemotherapy. With a median follow-up time of 46 months for the surviving 77 patients, the 3-year locoregional control, distant metastasis-free survival and overall survival rates were 89%, 74% and 66%, respectively. No treatment-related deaths occurred. Grade 3–4 toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of the patients, respectively. In conclusion, further improvement in survival and locoregional control is necessary, although our regimen showed acceptable toxicities. PMID:23192700

In vivo toxicity and antitumor activity of essential oils extract from agarwood (Aquilaria crassna).

PubMed

Dahham, Saad Sabbar; Hassan, Loiy E Ahmed; Ahamed, Mohamed B Khadeer; Majid, Aman Shah Abdul; Majid, Amin Malik Shah Abdul; Zulkepli, Nik Noriman

2016-07-22

Aquilaria crassna has been used in traditional Asian medicine to treat vomiting, rheumatism, asthma, and cough. Furthermore, earlier studies from our laboratory have revealed that the essential oil extract from agarwood inhibited colorectal carcinoma cells. Despite of the wide range of ethno-pharmacological uses of agarwood, its toxicity has not been previously evaluated through systematic toxicological studies. Therefore, the potential safety of essential oil extract and its in vivo anti-tumor activity had been investigated. In the acute toxicity study, Swiss female mice were given a single dose of the essential oil extract at 2000 mg/kg/day orally and screened for two weeks after administration. Meanwhile, in the sub-chronic study, two different doses of the extract were administered for 28 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological parameters were monitored during the study. Other than that, in vivo anti-tumor study was assessed by using subcutaneous tumors model established in nude mice. The acute toxicity study showed that the LD50 of the extract was greater than 2000 mg/kg. In the repeated dose for 28-day oral toxicity study, the administration of 100 mg/kg and 500 mg/kg of essential oil per body weight revealed insignificant difference in food and water intakes, bodyweight change, hematological and biochemical parameters, relative organ weights, gross findings or histopathology compared to the control group. Nevertheless, the essential oil extract, when supplemented to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells. Collectively, the data obtained indicated that essential oil extract from agarwood might be a safe material, and this essential oil is suggested as a potential anti-colon cancer candidate.

Curative Chemoradiotherapy in Patients With Stage IVB Cervical Cancer Presenting With Paraortic and Left Supraclavicular Lymph Node Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Ji-Yoon; Kim, Joo-Young; Kim, Jin Hee

2012-11-01

Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with curative intent in patients with stage IVB cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. Methods and Materials: The medical records of 25 patients with both paraortic and left supraclavicular lymph nodal metastases (group I) were reviewed and compared with those of 101 women with paraortic lymph node metastases alone (group II). Group I received a mean 59.4 Gy to the paraortic and left supraclavicular areas and 50.4 Gy to the pelvis, followed by 30 Gy of high-dose-rate brachytherapy in 6 fractions. Group IImore » received the same dose to the paraortic area and pelvis followed by intracavitary brachytherapy. All patients received platinum-based chemotherapy simultaneously. Results: Of the 25 patients in group I, 16 (64%) experienced acute grade 3-4 hematologic toxicities, and 1 had a late grade 3 genitourinary toxicity. Complete responses, including the primary mass and pelvic, paraortic, and left supraclavicular lymph nodes, were observed in 13 patients (52%). At a median follow-up of 32 months for surviving patients, 3 experienced in-field failure, 6 showed distant failure, and 9 showed both. The 3-year overall and disease-free survival rates were 49% and 33%, respectively. In comparison, of the 101 patients in group II, 16 showed in-field failure, 14 experienced distant failure, and 11 showed both. The 3-year overall and disease-free survival rates were 69% and 57%, respectively. Conclusions: Curative CCRT is feasible in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph nodal metastases, with acceptable late toxicity and high response rates, despite high rates of acute hematologic toxicity.« less

Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: optimal compliance and promising 4-year results.

PubMed

Ponzanelli, Anna; Vigo, Viviana; Marcenaro, Michela; Bacigalupo, Almalina; Gatteschi, Beatrice; Ravetti, Jean-Luis; Corvò, Renzo; Benasso, Marco

2008-08-01

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.

Biomarkers of Type II Synthetic Pyrethroid Pesticides in Freshwater Fish

PubMed Central

2014-01-01

Type II synthetic pyrethroids contain an alpha-cyano group which renders them more neurotoxic than their noncyano type I counterparts. A wide array of biomarkers have been employed to delineate the toxic responses of freshwater fish to various type II synthetic pyrethroids. These include hematological, enzymatic, cytological, genetic, omic and other types of biomarkers. This review puts together the applications of different biomarkers in freshwater fish species in response to the toxicity of the major type II pyrethroid pesticides and assesses their present status, while speculating on the possible future directions. PMID:24868555

Biomarkers of type II synthetic pyrethroid pesticides in freshwater fish.

PubMed

Kaviraj, Anilava; Gupta, Abhik

2014-01-01

Type II synthetic pyrethroids contain an alpha-cyano group which renders them more neurotoxic than their noncyano type I counterparts. A wide array of biomarkers have been employed to delineate the toxic responses of freshwater fish to various type II synthetic pyrethroids. These include hematological, enzymatic, cytological, genetic, omic and other types of biomarkers. This review puts together the applications of different biomarkers in freshwater fish species in response to the toxicity of the major type II pyrethroid pesticides and assesses their present status, while speculating on the possible future directions.

Inhalation Toxicity of Cogenerated Graphite Flake and Fog Oil Smoke in the Brown-Headed Cowbird and the Red-Winged Blackbird, Size-Specific Inhalation Surrogates for the Red-Cockaged Woodpecker

DTIC Science & Technology

2005-01-01

graphite flakes for infrared obscuration are being deployed for training scenarios. The effect of this combination on avian species was unknown. Our...Hematological response was normal and no toxic effects in eryth- rocytes or leukocytes were found. White blood cell counts, spleen weights, and incidence of...5 List of Figures and Tables Figures 1. Exposure system used for testing the effects of fog oil and graphite flake aerosols on avian health

Doxorubicin and ifosfamide combination chemotherapy in previously treated acute leukemia in adults: a Southwest Oncology Group pilot study.

PubMed

Ryan, D H; Bickers, J N; Vial, R H; Hussein, K; Bottomley, R; Hewlett, J S; Wilson, H E; Stuckey, W J

1980-01-01

The Southwest Oncology Group did a limited institutional pilot study of the combination of doxorubicin and ifosfamide in the treatment of previously treated adult patients with acute leukemia. Thirty-four patients received one or two courses of the combination. All patients had received prior chemotherapy and 32 had received prior anthracycline chemotherapy. Three patients died before their responses could be fully evaluated. Fourteen patients achieved complete remission (41%) and one patient achieved partial remission. The complete remission rate was 27% for patients with acute myeloblastic leukemia (myelomonoblastic leukemia, monoblastic leukemia, and erythroleukemia) and 89% for patients with acute lymphocytic and undifferentiated leukemia (ALL). Toxic effects included severe hematologic reactions in 33 of 34 patients, hematuria in six patients, altered sensorium in one patient, and congestive heart failure in one patient. The safety of the combination was established and toxic side effects of this therapy were tolerable. The 89% complete remission rate for previously treated patients with ALL suggests that the combination of doxorubicin and ifosfamide may be particularly effective in ALL.

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models

PubMed Central

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-01-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

Mechanism of deoxynivalenol effects on the reproductive system and fetus malformation: Current status and future challenges.

PubMed

Yu, Miao; Chen, Liangkai; Peng, Zhao; Nüssler, Andreas K; Wu, Qinghua; Liu, Liegang; Yang, Wei

2017-06-01

Deoxynivalenol (DON) is a toxic fungal secondary metabolite produced by molds of the Fusarium genus, and it is known to cause a spectrum of diseases both in humans and animals, such as emesis, diarrhea, anorexia, immunotoxicity, hematological disorders, impairment of maternal reproduction, and fetal development. The recently revealed teratogenic potential of DON has received much attention. In various animal models, it has been shown that DON led to skeletal deformities of the fetus. However, the underlying mechanisms are not yet fully understood, and toxicological data are also scarce. Several animal research studies highlight the potential link between morphological abnormalities and changes of autophagy in the reproductive system. Because autophagy is involved in fetal development, maintenance of placental function, and bone remodeling, this mechanism has become a high priority for future research. The general aim of the present review is to deliver a comprehensive overview of the current state of knowledge of DON-induced reproductive toxicity in different animal models and to provide some prospective ideas for further research. The focus of the current review is to summarize toxic and negative effects of DON exposure on the reproductive system and the potential underlying molecular mechanisms in various animal models. Copyright © 2017 Elsevier B.V. All rights reserved.

Data Summary for Trinitrotoluene

DTIC Science & Technology

1986-09-01

carious and noncarious tooth injury and periodontal and oral cavity mucous membrane disease ; cataract formation; and biochemical changes, e.g...nephrotoxicity, causing an increase in renal filtration Fates; neurotoxicity, indicated by neurasthenia and polyneuritis; pancreatic 11 toxicity...5.0 to 50 mg/kg resulted in hematological, hepatic, neurological, splenic, pancreatic , and biochemical - dysfunctions similar to those previously

Fulminant Liver Failure in a Child With β-Thalassemia on Deferasirox: A Case Report.

PubMed

Ramaswami, Archie; Rosen, Danya J; Chu, Jaime; Wistinghausen, Birte; Arnon, Ronen

2017-04-01

Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as β-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with β-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX.

The toxicology and safety of apple polyphenol extract.

PubMed

Shoji, T; Akazome, Y; Kanda, T; Ikeda, M

2004-06-01

Apple polyphenol extract has strong antioxidant activity and various physiological functions, and is used in Japan as a food additive and nutritional supplements. Here, we tested the consumption safety of Applephenon, which is a polyphenol extract produced from unripe apples. The Ames test without S9 mixture revealed that Applephenon, had slight mutagenicity at a high concentration of 2500 microg/plate; however, both chromosomal aberration test and the micronucleus test found no significant mutagenicity. Furthermore, an acute oral-toxicity test, and a 90-day subchronic-toxicity test showed no significant hematological, clinical, chemical, histopathological, or urinary effects at a dose of 2000 mg/kg. These results confirm that Applephenon is safe and no toxic at average dietary level.

Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

PubMed

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R; Bahrami-Samani, Ali

2015-01-01

(177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using (177)Lu-EDTMP for MBP palliation. (177)Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. (177)Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. (177)Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis.

Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

PubMed Central

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

2015-01-01

177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis. PMID:26097421

Physical Activity as a Nonpharmacological Symptom Management Approach in Myeloproliferative Neoplasms: Recommendations for Future Research

PubMed Central

Eckert, Ryan; Huberty, Jennifer; Gowin, Krisstina; Mesa, Ruben; Marks, Lisa

2016-01-01

Purpose: Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. Methods: A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. Results: There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. Conclusions: Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients. PMID:27458250

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chera, Bhishamjit S., E-mail: bchera@med.unc.edu; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Amdur, Robert J.

Purpose: To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus–associated oropharyngeal squamous cell carcinoma. Methods and Materials: The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m{sup 2}). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless ofmore » radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. Results: The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. Conclusions: The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. (ClinicalTrials.gov) ID: (NCT01530997).« less

The effects of feeding clinoptilolite on hematology, performance, and health of newborn lambs.

PubMed

Norouzian, M A; Valizadeh, R; Khadem, A A; Afzalzadeh, A; Nabipour, A

2010-11-01

The effects of feeding clinoptilolite on hematology, performance, and health of newborn Balouchi lambs were evaluated in this experiment. In a completely randomized design, 30 newborn lambs were allocated to three groups and fed by basal diet (C0; without clinoptilolite) and C1 and C2 (the basal diet plus 1.5% and 3% clinoptilolite, respectively, for 6 weeks (3 weeks before and 3 weeks after weaning)). Blood samples were taken from all lambs, at the time when the animals were allocated to the experimental diet and at the end of each week of experiment, and analyzed for hematology, plasma fibrinogen, and total protein. Performance and health of all lambs were measured. Fecal consistency score and diarrhea severity were evaluated. There was no difference between lambs in case of hematological parameters. Lambs fecal consistency score and severity of diarrhea were lowest (P < 0.05) for lambs on C1 and C2 and highest for lambs on C0. Dry matter intake and feed conservation ratio were similar between the groups of lambs fed by different diets, but daily gain of lambs differed significantly (P < 0.05) and was higher in C2. It was concluded that addition of 3% clinoptilolite to starter diet of newborn lamb can reduce incidence and severity of diarrhea, although its effect on hematology and performance was negligible.

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

PubMed

Aisner, J; Goutsou, M; Maurer, L H; Cooper, R; Chahinian, P; Carey, R; Skarin, A; Slawson, R; Perry, M C; Green, M R

1992-08-01

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

PubMed

Puzanov, I; Diab, A; Abdallah, K; Bingham, C O; Brogdon, C; Dadu, R; Hamad, L; Kim, S; Lacouture, M E; LeBoeuf, N R; Lenihan, D; Onofrei, C; Shannon, V; Sharma, R; Silk, A W; Skondra, D; Suarez-Almazor, M E; Wang, Y; Wiley, K; Kaufman, H L; Ernstoff, M S

2017-11-21

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles.

PubMed

Xie, Shuyu; Wang, Fenghua; Wang, Yan; Zhu, Luyan; Dong, Zhao; Wang, Xiaofang; Li, Xihe; Zhou, Wenzhong

2011-11-20

Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD(50)) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity categories of chemicals. Moreover, HCO-SLN significantly decreased the toxicity of tilmicosin. Normal clinic dosage of Til-HCO-SLN is safe as evaluated by acute toxicity.

Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

PubMed Central

2011-01-01

Background Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Methods Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD50) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. Results After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. Conclusions The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity categories of chemicals. Moreover, HCO-SLN significantly decreased the toxicity of tilmicosin. Normal clinic dosage of Til-HCO-SLN is safe as evaluated by acute toxicity. PMID:22098626

Acute and sub-acute oral toxicity of Dracaena cinnabari resin methanol extract in rats.

PubMed

Al-Afifi, Nashwan Abdullah; Alabsi, Aied Mohammed; Bakri, Marina Mohd; Ramanathan, Anand

2018-02-05

Dracaena cinnabari (DC) is a perennial tree that located on the Southern coast of Yemen native to the Socotra Island. This tree produces a deep red resin known as the Dragon's blood, the Twobrother's Blood or Damm Alakhwain. The current study performed to evaluate the safety of the DC resin methanol extract after a single or 28 consecutive daily oral administrations. In assessing the safety of DC resin methanol extract, acute and sub-acute oral toxicity tests performed following OECD guidelines 423 and 407, respectively, with slight modifications. In acute oral toxicity test, DC resin methanol extract administered to female Sprague Dawley rats by oral gavage at a single dose of 300 and 2000 mg/kg body weight. Rats observed for toxic signs for 14 days. In sub-acute oral toxicity test, DC resin methanol extract administered to the rats by oral gavage at 500, 1000, and 1500 mg/kg body weight daily up to 28 days to male and female Spradgue Dawley rats. The control and high dose in satellite groups were also maintained and handled as the previous groups to determine the late onset toxicity of DC resin methanol extract. At the end of each test, hematological and biochemical analysis of the collected blood were performed as well as gross and microscopic pathology. In acute oral toxicity, no treatment-related death or toxic signs were observed. It revealed that the DC resin methanol extract could be well tolerated up to the dose 2000 mg/kg body weight and could be classified as Category 5. The sub-acute test observations indicated that there are no treatment-related changes up to the high dose level compared to the control. Food consumption, body weight, organ weight, hematological parameters, biochemical parameters and histopathological examination (liver, kidney, heart, spleen and lung) revealed no abnormalities. Water intake was significantly higher in the DC resin methanol extract treated groups compared to the control. This study demonstrates tolerability of DC resin methanol extract administered daily for 28 days up to 1500 mg/kg dose.

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

PubMed Central

Barrientos, Jacqueline C.; Barr, Paul M.; Flinn, Ian W.; Burger, Jan A.; Tran, Anh; Clow, Fong; James, Danelle F.; Graef, Thorsten; Friedberg, Jonathan W.; Rai, Kanti; O’Brien, Susan

2015-01-01

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. PMID:25755291

A Phase 2 Study of Concurrent Fludarabine and Rituximab for the Treatment of Marginal Zone Lymphomas

PubMed Central

Brown, Jennifer R; Friedberg, Jonathan W.; Feng, Yang; Scofield, Sarah; Phillips, Kimberly; Cin, Paola Dal; Joyce, Robin; Takvorian, Ronald W; Fisher, David C; Fisher, Richard I; Liesveld, Jane; Marquis, Diana; Neuberg, Donna; Freedman, Arnold S

2009-01-01

SUMMARY The marginal zone lymphomas are a recently defined group of related diseases likely arising from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric MALT has been largely limited to retrospective case series. We therefore undertook this prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas. 26 patients were enrolled, 14 with nodal MZL, 8 with MALT lymphomas and 4 with splenic MZL; 81% were receiving initial systemic therapy. Only 58% (95% CI 37–77%) of patients completed the planned six cycles, due to significant hematologic, infectious and allergic toxicity. Four late toxic deaths occurred due to infections (15% (95% CI 4.3–35%), two related to delayed bone marrow aplasia and two related to MDS. Nonetheless, the ORR was 85% (95% CI 65–96%), with 54% CRs. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI, 63–96%). We conclude that although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of marginal zone lymphomas, the significant hematologic and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study marginal zone lymphomas as a separate entity. PMID:19344412

Sub-chronic oral toxicity of Cuminum cyminum L.'s essential oil in female Wistar rats.

PubMed

Taghizadeh, Mohsen; Ostad, Seyed Naser; Asemi, Zatollah; Mahboubi, Mohaddese; Hejazi, Sara; Sharafati-Chaleshtori, Reza; Rashidi, Aliakbar; Akbari, Hosein; Sharifi, Nasrin

2017-08-01

The current study was performed to evaluate the toxicity of Cuminum cyminum L. (C. cyminum)'s essential oil after 23 days and 45 days of repeated oral administration in female Wistar rats. A total of 80 healthy female Wistar rats were randomly selected and divided into 4 groups. The rats were gavaged with C. cyminum's essential oil at dose levels of 0, 250, 500 and 1000 mg/kg/day. Clinical signs, body weight, hematology, serum biochemistry and organ histopathology were assessed once after 23 days and again after 45 days passed from the start of the intervention. Oral administration of C. cyminum's essential oil had no observed adverse effects on clinical signs, mortality, body weight, hematology, biochemistry and organ histology (liver, kidneys, spleen and lungs) in a sample of healthy female Wistar rats after 23 days and 45 days from the start of the study. However, an increase in serum levels of alanine transaminase (ALT) was found only at dose level of 1000 mg/kg/d C. cyminum's essential oil, after the 23-days interval. We conservatively defined the non-observed adverse effect level (NOAEL) for C. cyminum's essential oil as 500 mg/kg/d in female Wistar rats. The present study results should be treated with cautious in terms of the other organs' toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

PubMed

Jeyapalan, Suriya; Boxerman, Jerrold; Donahue, John; Goldman, Marc; Kinsella, Timothy; Dipetrillo, Thomas; Evans, Devon; Elinzano, Heinrich; Constantinou, Maria; Stopa, Edward; Puthawala, Yakub; Cielo, Deus; Santaniello, Alyson; Oyelese, Adetokunbo; Mantripragada, Kalyan; Rosati, Kayla; Isdale, Debora; Safran, Howard

2014-10-01

Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

Inhalation Toxicity of Bisphenol A and Its Effect on Estrous Cycle, Spatial Learning, and Memory in Rats upon Whole-Body Exposure

PubMed Central

Chung, Yong Hyun; Han, Jeong Hee; Lee, Sung-Bae; Lee, Yong-Hoon

2017-01-01

Bisphenol A (BPA) is a monomer used in a polymerization reaction in the production of polycarbonate plastics. It has been used in many consumer products, including plastics, polyvinyl chloride, food packaging, dental sealants, and thermal receipts. However, there is little information available on the inhalation toxicity of BPA. Therefore, the aim of this study was to determine its inhalation toxicity and effects on the estrous cycle, spatial learning, and memory. Sprague-Dawley rats were exposed to 0, 10, 30, and 90 mg/m3 BPA, 6 hr/day, 5 days/week for 8 weeks via whole-body inhalation. Mortality, clinical signs, body weight, hematology, serum chemistry, estrous cycle parameters, performance in the Morris water maze test, and organ weights, as well as gross and histopathological findings, were compared between the control and BPA exposure groups. Statistically significant changes were observed in serum chemistry and organ weights upon exposure to BPA. However, there was no BPA-related toxic effect on the body weight, food consumption, hematology, serum chemistry, organ weights, estrous cycle, performance in the Morris water maze test, or gross or histopathological lesions in any male or female rats in the BPA exposure groups. In conclusion, the results of this study suggested that the no observable adverse effect level (NOAEL) for BPA in rats is above 90 mg/m3/6 hr/day, 5 days/week upon 8-week exposure. Furthermore, BPA did not affect the estrous cycle, spatial learning, or memory in rats. PMID:28503266

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline.

PubMed

Brahmer, Julie R; Lacchetti, Christina; Schneider, Bryan J; Atkins, Michael B; Brassil, Kelly J; Caterino, Jeffrey M; Chau, Ian; Ernstoff, Marc S; Gardner, Jennifer M; Ginex, Pamela; Hallmeyer, Sigrun; Holter Chakrabarty, Jennifer; Leighl, Natasha B; Mammen, Jennifer S; McDermott, David F; Naing, Aung; Nastoupil, Loretta J; Phillips, Tanyanika; Porter, Laura D; Puzanov, Igor; Reichner, Cristina A; Santomasso, Bianca D; Seigel, Carole; Spira, Alexander; Suarez-Almazor, Maria E; Wang, Yinghong; Weber, Jeffrey S; Wolchok, Jedd D; Thompson, John A

2018-06-10

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

75 FR 33166 - Extension of Expiration Dates for Several Body System Listings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-11

... Impairment, Hematological Disorders, Musculoskeletal System, Mental Disorders, Neurological, and Respiratory... be effective: Growth Impairment (100.00); Respiratory System (3.00 and 103.00); Hematological... listings (70 FR 53323 (2005)), the respiratory listings (70 FR 19358 (2005)), the cardiovascular listings...

Targeting BET bromodomain proteins in solid tumors

PubMed Central

Sahai, Vaibhav; Redig, Amanda J.; Collier, Katharine A.; Eckerdt, Frank D.; Munshi, Hidayatullah G.

2016-01-01

There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors. PMID:27283767

Hemoglobin and hematocrit values in the fish Oreochromis mossambicus (Peters) after short term exposure to copper and mercury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cyriac, P.J.; Antony, A.; Nambisan, P.N.K.

1989-08-01

Hematology is used as an index of health status in a number of fish species. Hematological changes have been detected following different types of stress conditions like exposure to pollutants, diseases, hypoxia, etc. Copper and mercury are two known aquatic pollutants. Though copper is an essential micro-nutrient, it is highly toxic at high concentrations. Mercury has no biological function to serve and causes serious impairment in the metabolic and physiological functions of the body. In this paper hematocrit and hemoglobin (Hb) values in the fish Oreochromis mossambicus separately exposed to two different sublethal concentrations of copper and mercury for amore » period of 168 h are reported.« less

Value of innovation for hematologic malignancies.

PubMed

Monia, Marchetti

2016-01-01

Several novel drugs are dramatically improving both lifespan and quality-of-life of patients with blood cancers. Prolonged disease duration and increased treatment costs for hematologic malignancies impose a relevant economic burden onto healthcare services, despite the low incidence of blood cancers. Therefore, an appropriate paradigm for valuing 'innovation' is urgently required in order to refine pricing and reimbursement decisions. Cost-per-QALY-gained is still the standard metric for assessing the 'incremental' value of new drugs; however, the high number of 'comparator' therapies and the huge variety of treatment sequences make plain two-treatment comparisons sub-optimal, while multiple-treatment and multiple-sequence comparisons require complex and less-transparent decision models. A repository of standard backbones for decision models might allow benchmarking and comparability among cost-effectiveness analyses; however, an international effort is required to build it up. Deontology recommends that hematologists act in optimizing healthcare resources while preserving patient-physician alliance, but clinical practice guidelines do not support doctors in balancing cost against clinical outcomes. Decision models of chronic blood cancers unexpectedly proved that cost might be an appropriate value for innovation if treatments avoided severe toxicity and further lines of treatments, despite the eventually long duration of treatment and the competing risk of death due to comorbidity and old age. The improved transparency of decision models allows sharing of relevant structural and analytic parameters (i.e., time horizon, comparator treatments, hierarchy of end-point, assumptions, source of data, sub-group analyses) by stakeholders, physicians and patients, making health economics a noble 'translator' of values for innovation.

Current and emerging treatment options in the management of lupus

PubMed Central

Jordan, Natasha; D’Cruz, David

2016-01-01

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with variable clinical manifestations. While the clearest guidelines for the treatment of SLE exist in the context of lupus nephritis, patients with other lupus manifestations such as neuropsychiatric, hematologic, musculoskeletal, and severe cutaneous lupus frequently require immunosuppression and/or biologic therapy. Conventional immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are widely used in the management of SLE with current more rationalized treatment regimens optimizing the use of these agents while minimizing potential toxicity. The advent of biologic therapies has advanced the treatment of SLE particularly in patients with refractory disease. The CD20 monoclonal antibody rituximab and the anti-BLyS agent belimumab are now widely in use in clinical practice. Several other biologic agents are in ongoing clinical trials. While immunosuppressive and biologic agents are the foundation of inflammatory disease control in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected. PMID:27529058

Intestinal mucositis: mechanisms and management.

PubMed

Keefe, Dorothy M

2007-07-01

To describe the advances in the rapidly evolving field of intestinal (or alimentary) mucositis during the past year. Major advances have been made in both the clinical and preclinical setting, with the publication of a suite of articles regarding the pathobiology and management of mucositis, as well as several articles on important basic research in the area. The mechanism of mucositis development is now understood to be much more complex than previously thought, with an interplay of host and drug factors leading to overt damage, and variation in manifestation of that damage depending on the specific region of the gut. The MASCC/ISOO management guidelines for mucositis have been updated: a recommendation for the use of palifermin in the hematology transplant setting has been added, and a couple of previous recommendations have been revoked. This marks an important milestone in mucositis, as it is the first time a drug has been available that substantially reduces the occurrence and severity of mucositis. There is still much to be done to abolish the severe toxicity of chemotherapy and radiotherapy; however, progress is accelerating, and new targeted drugs are becoming available.

In vivo assessment of toxicity and pharmacokinetics of methylglyoxal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghosh, Manju; Talukdar, Dipa; Ghosh, Swapna

2006-04-01

Previous in vivo studies from several laboratories had shown remarkable curative effect of methylglyoxal on cancer-bearing animals. In contrast, most of the recent in vitro studies have assigned a toxic role for methylglyoxal. The present study was initiated with the objective to resolve whether methylglyoxal is truly toxic in vivo and to reassess its therapeutic potential. Four species of animals, both rodent and non-rodent, were treated with different doses of methylglyoxal through oral, subcutaneous and intravenous routes. Acute (treatment for only 1 day) toxicity tests had been done with mouse and rat. These animals received 2, 1 and 0.3 gmore » of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Chronic (treatment for around a month) toxicity test had been done with mouse, rat, rabbit and dog. Mouse, rat and dog received 1, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Rabbit received 0.55, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. It had been observed that methylglyoxal had no deleterious effect on the physical and behavioral pattern of the treated animals. Fertility and teratogenecity studies were done with rats that were subjected to chronic toxicity tests. It had been observed that these animals produced healthy litters indicating no damage of the reproductive systems as well as no deleterious effect on the offspring. Studies on several biochemical and hematological parameters of methylglyoxal-treated rats and dogs and histological studies of several organs of methylglyoxal-treated mouse were performed. These studies indicated that methylglyoxal had no apparent deleterious effect on some vital organs of these animals. A detailed pharmacokinetic study was done with mouse after oral administration of methylglyoxal. The effect of methylglyoxal alone and in combination with creatine and ascorbic acid on cancer-bearing animals had been investigated by measuring the increase in life span and tumor cell growth inhibition. The results indicated that anticancer effect of methylglyoxal was significantly augmented by ascorbic acid and further augmented by ascorbic acid and creatine. Nearly 80% of the animals treated with methylglyoxal plus ascorbic acid plus creatine were completely cured and devoid of any malignant cells within the peritoneal cavity.« less

[Hypersensitivity to dacarbazine in patients with metastatic malignant melanoma].

PubMed

Levy, A; Guitera, P; Kerob, D; Ollivaud, L; Archimbaud, A; Dubertret, L; Basset-Seguin, N

2006-02-01

Dacarbazine (DTIC) is the first-line chemotherapy for metastatic malignant melanoma without cerebral metastasis. Its clinical and hematological safety is usually good. Hypersensitivity in hepatic failure patients is the most serious side effect described. This was a retrospective study of the prevalence of hypersensitivity in patients treated with DTIC for metastatic melanoma between 11/01/2002 and 10/31/2003. Hypersensitivity was diagnosed in the event of fever, hypereosinophilia (> 500/mm3) with or without liver dysfunction (> twice pre-therapeutic values). Clinical data, DTIC administration modalities, number of courses and clinical and laboratory safety data were recorded. Twenty patients were included, 11 women and 9 men of median age 58.6 years (22-82 years) with multiple metastases in all cases. DTIC was the first-line treatment for 19 patients, being administered for 4 days to 10 patients and for 1 day to the other 10 patients, depending on their overall health status. Five hypersensitivity-like manifestations were observed, all in the 4-day treatment group. In 3 patients, fever and hypereosinophilia were seen without liver dysfunction at D3 of the second course of treatment. In 2 patients, treatment was stopped after the second course because of disease progression. In the third patient, 4 courses were given with recurrence of symptoms, although the latter were controlled during the fifth course with corticosteroids and antihistamines given 15 minutes before the start of treatment. Two patients experienced severe forms of hypersensitivity with fever, hypereosinophilia, liver dysfunction (cytolysis and cholestasis) and delayed medullar aplasia, after the first and second course respectively. In one patient, bone marrow examination showed a block at the promyelocytic stage consistent with a toxic etiology. Treatment with DTIC was stopped, and all signs regressed with symptomatic treatment. Hypersensitivity with DTIC seems to be frequent, being observed in 20% of our patients, with early onset (after the first or second course) and absence of dose-dependence. We describe for the first time two cases of medullar aplasia occurring in association with DTIC hypersensitivity. During phase I studies, the hematologic toxicity of DTIC was moderate, rarely affecting red cells, and was observed with higher doses than those used in metastatic malignant melanoma. We suggest that this aplasia forms part of the signs of hypersensitivity because of the bone marrow morphology, the existence of anemia and concomitant resolution with all the others signs of hypersensitivity. Laboratory monitoring (NFS, liver enzymes) is thus justified, particularly after the first and second courses of DTIC. In case of fever and hypereosinophilia without liver dysfunction, DTIC may be continued together with symptomatic treatment. In the event of hepatic dysfunction, and of course severe hematological disorders, potentially fatal complications can occur and treatment must be stopped.

Relating tumor score to hematology in green turtles with fibropapillomatosis in Hawaii

USGS Publications Warehouse

Work, Thierry M.; Balazs, George H.

1999-01-01

The relationship between hematologic status and severity of tumor affliction in green turtles (Chelonia mydas) with fibropapillomatosis (FP) was examined. During 1 wk periods in July 1997 and July 1998, we bled 108 free-ranging green turtles from Pala'au (Molokai, Hawaii, USA) where FP is endemic. Blood was analyzed for hematocrit, estimated total solids, total white blood cell (WBC) count and differential WBC count. Each turtle was assigned a subjective tumor score ranging from 0 (no visible external tumors) to 3 (heavily tumored) that indicated the severity of FP. There was a progressive increase in monocytes and a decrease in all other hematologic parameters except heterophils and total numbers of white blood cells as tumor score increased. These data indicate that tumor score can relate to physiologic status of green turtles afflicted with FP, and that tumor score is a useful field monitor of severity of FP in this species.

Ethical considerations in genomic testing for hematologic disorders.

PubMed

Marron, Jonathan M; Joffe, Steven

2017-07-27

As our technological capacities improve, genomic testing is increasingly integrating into patient care. The field of clinical hematology is no exception. Genomic testing carries great promise, but several ethical issues must be considered whenever such testing is performed. This review addresses these ethical considerations, including issues surrounding informed consent and the uncertainty of the results of genomic testing; the challenge of incidental findings; and possible inequities in access to and benefit from such testing. Genomic testing is likely to transform the practice of both benign and malignant hematology, but clinicians must carefully consider these core ethical issues in order to make the most of this exciting and evolving technology. © 2017 by The American Society of Hematology.

An assessment of hematological and biochemical responses in the tropical fish Epinephelus stoliczkae of Chabahar Bay and Gulf of Oman under chromium exposure: ecological and experimental tests.

PubMed

Sadeghi, Parvin; Savari, Ahmad; Movahedinia, Abdolali; Safahieh, Alireza; Azhdari, Danial

2014-05-01

The aim of this investigation was to evaluate the effect of chromium on hematological and biochemical parameters in Epaulet Grouper, Epinephelus stoliczkae of Chabahar Bay and Gulf of Oman by ecological and experimental tests. Spatial evaluation of ecological test results showed these parameters had significant difference among some sampling sites. Examination of hematological and biochemical profiles on Epaulet Grouper was performed after 0.5, 1, 7, 14, and 21 days of chromium exposure (3.6, 7.31 and 14.6 mg/L). Experimental test results of chromium induce indicated the significant decrease in MCV, MCH, neutrophils, basophils, plasma protein and significant increase in MCHC, lymphocytes, monocytes, eosinophils and a biphasic trend in Hb, Ht, RBC, WBC, and glucose (p < 0.05). Cellular and nuclear axis, cytoplasmic volume, cell and nuclear volume, and surface area were significantly different for ecological and experimental results (p < 0.05). It was concluded that these parameters are sensitive in monitoring the toxicity of chromium concentrations.

Effects of blood lead level on biochemical and hematological parameters in children with neurological diseases of Western Maharashtra, India.

PubMed

Pratinidhi, Shilpa A; Patil, Arun J; Behera, Manaskumar; Patil, Maya; Ghadage, Dnyaneshwari P; Pratinidhi, Asha K

2014-05-01

Lead is found in small but appreciable quantities in air, soil, drinking water, and food. Exposure to such amounts of lead does not lead to acute lead toxicity but produces subtle effects particularly in children. The aim of this study was to investigate the effects of blood lead level on biochemical and hematological parameters in children with neurological diseases in Western Maharashtra, India, and to estimate the blood lead level by liver and kidney function tests and hematological parameters in children with neurological disorders admitted to the pediatric ward and compare them with healthy controls. In this study, 30 children with various neurological disorders admitted to the pediatric ward of Smt. Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India, were compared with 30 age- and sex-matched healthy controls. Four milliliters of venous blood was collected for estimation of blood lead level, and biochemical and hematological parameters were determined using standard methods. Blood lead level was significantly increased in the study group (p<0.01, 65.38%) compared to that in the control group. When different neurological conditions were grouped into three groups according to blood lead levels, there was a significant difference between the groups. All other biochemical and hematological parameters were not significantly altered in the study group as compared to the control group. Neurologically challenged children are more vulnerable to lead intoxication. It is imperative for the parents to take extra care of their children's food habits and limit hand-to-mouth activities to prevent lead intoxication.

Reduced Toxicity With Intensity Modulated Radiation Therapy (IMRT) for Desmoplastic Small Round Cell Tumor (DSRCT): An Update on the Whole Abdominopelvic Radiation Therapy (WAP-RT) Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Desai, Neil B.; Stein, Nicholas F.; LaQuaglia, Michael P.

2013-01-01

Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare malignancy typically involving the peritoneum in young men. Whole abdominopelvic radiation therapy (WAP-RT) using conventional 2-dimensional (2D) radiation therapy (RT) is used to address local recurrence but has been limited by toxicity. Our objectives were to assess the benefit of intensity modulated radiation therapy (IMRT) on toxicity and to update the largest series on radiation for DSRCT. Methods and Materials: The records of 31 patients with DSRCT treated with WAP-RT (22 with 2D-RT and 9 with IMRT) between 1992 and 2011 were retrospectively reviewed. All received multi-agent chemotherapy and maximalmore » surgical debulking followed by 30 Gy of WAP-RT. A further focal boost of 12 to 24 Gy was used in 12 cases. Boost RT and autologous stem cell transplantation were nearly exclusive to patients treated with 2D-RT. Toxicities were assessed with the Common Terminology Criteria for Adverse Events. Dosimetric analysis compared IMRT and simulated 2D-RT dose distributions. Results: Of 31 patients, 30 completed WAP-RT, with a median follow-up after RT of 19 months. Acute toxicity was reduced with IMRT versus 2D-RT: P=.04 for gastrointestinal toxicity of grade 2 or higher (33% vs 77%); P=.02 for grade 4 hematologic toxicity (33% vs 86%); P=.01 for rates of granulocyte colony-stimulating factor; and P=.04 for rates of platelet transfusion. Post treatment red blood cell and platelet transfusion rates were also reduced (P=.01). IMRT improved target homogeneity ([D05-D95]/D05 of 21% vs 46%) and resulted in a 21% mean bone dose reduction. Small bowel obstruction was the most common late toxicity (23% overall). Updated 3-year overall survival and progression-free survival rates were 50% and 24%, respectively. Overall survival was associated with distant metastasis at diagnosis on multivariate analysis. Most failures remained intraperitoneal (88%). Conclusions: IMRT for consolidative WAP-RT in DSRCT improves hematologic toxicity in particular. Although the long-term efficacy of current treatment options remains disappointing, the improved therapeutic index of IMRT may aid in generalizing its use and allowing the addition of novel approaches such as intraperitoneal immunotherapy.« less

Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?

PubMed Central

Cierpicki, Tomasz; Grembecka, Jolanta

2015-01-01

Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein-protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of pre-clinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of protein-protein interactions highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein-protein interfaces, with the goal to address ‘druggability’ of new PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new protein-protein interactions and evaluate prospects and limits of the research in this field. We conclude that not all PPIs are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new protein-protein interactions. PMID:25510283

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.

PubMed

Kratochwil, Clemens; Bruchertseifer, Frank; Giesel, Frederik L; Weis, Mirjam; Verburg, Frederik A; Mottaghy, Felix; Kopka, Klaus; Apostolidis, Christos; Haberkorn, Uwe; Morgenstern, Alfred

2016-12-01

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225 Ac-PSMA-617 therapy. 68 Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225 Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68 Ga-PSMA-11 PET/CT. Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. Targeted α-therapy with 225 Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Safety assessment of freeze-dried powdered Tenebrio molitor larvae (yellow mealworm) as novel food source: Evaluation of 90-day toxicity in Sprague-Dawley rats.

PubMed

Han, So-Ri; Lee, Byoung-Seok; Jung, Kyung-Jin; Yu, Hee-Jin; Yun, Eun-Young; Hwang, Jae Sam; Moon, Kyoung-Sik

2016-06-01

Worldwide demand for novel food source has grown and edible insects are a promising food sources for humans. Tenebrio molitor, as known as yellow mealworm, has advantages of being rich in protein, and easy to raise as a novel food source. The objective of this study was to evaluate subchronic toxicity, including potential hypersensitivity, of freeze-dried powdered T. molitor larvae (fdTML) in male and female Sprague-Dawley rats. The fdTML was administered orally once daily at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 90 days. A toxicological assessment was performed, which included mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings, histopathologic examination and allergic reaction. There were no fdTML- related findings in clinical signs, urinalysis, hematology and serum chemistry, gross examination, histopathologic examination or allergic reaction. In conclusion, the No Observed Adverse Effect Level (NOAEL) for fdTML was determined to be in excess of 3000 mg/kg/day in both sexes of rats under the experimental conditions of this study. Copyright © 2016 Elsevier Inc. All rights reserved.

A subchronic dietary toxicity study of rice hull fiber in rats.

PubMed

Gao, Yonglin; Shen, Jingyu; Yin, Jungang; Li, Chunmei; Fu, Chengyu; Cho, Susan

2013-01-01

We conducted a 90-day feeding study to investigate subchronic toxicity of rice hull fiber. Sprague Dawley rats were randomly divided into four groups; each received a diet containing 0%, 2.5%, 3.75% and 5.0% (w/w) rice hull fiber for 90days. Clinical observations were carried out daily, with weekly measurements of body weight and food consumption. We performed ophthalmic and histological examinations at termination. Blood and urine samples were collected to measure hematology and clinical chemistry parameters. No mortality, ophthalmic abnormalities, or adverse treatment-related effects were seen during clinical observations, hematological tests, or analyses of urine. Macroscopic or microscopic examinations of organs revealed no treatment related abnormalities. The only treatment related significant changes were reduced concentrations of fasting blood glucose (up to 17.6%) and cholesterol (up to 22.0%), typical benefits of dietary fiber, in males treated with 3.75 and 5% rice hull fiber. The no-observed-adverse-effect-level (NOAEL) for rice hull fiber was 5.0% for both genders (females, 3.80g/kg body weight/day; males, 4.11g/kg body weight/day). Copyright © 2012 Elsevier Ltd. All rights reserved.

Blood disorders typically associated with renal transplantation

PubMed Central

Yang, Yu; Yu, Bo; Chen, Yun

2015-01-01

Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival. PMID:25853131

Toxicologic assessment of a commercial decolorized whole leaf aloe vera juice, lily of the desert filtered whole leaf juice with aloesorb.

PubMed

Sehgal, Inder; Winters, Wallace D; Scott, Michael; David, Andrew; Gillis, Glenn; Stoufflet, Thaya; Nair, Anand; Kousoulas, Konstantine

2013-01-01

Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies-examined grossly and microscopically-that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks.

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

PubMed Central

Cunha-Júnior, Edézio Ferreira; Martins, Thiago Martino; Canto-Cavalheiro, Marilene Marcuzzo; Marques, Paulo Roberto; Portari, Elyzabeth Avvad; Coelho, Marsen Garcia Pinto; Netto, Chaquip Daher; Costa, Paulo Roberto Ribeiro; Sabino, Katia Costa de Carvalho

2016-01-01

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis. PMID:27067332

Toxicologic Assessment of a Commercial Decolorized Whole Leaf Aloe Vera Juice, Lily of the Desert Filtered Whole Leaf Juice with Aloesorb

PubMed Central

Winters, Wallace D.; Scott, Michael; David, Andrew; Gillis, Glenn; Stoufflet, Thaya; Nair, Anand; Kousoulas, Konstantine

2013-01-01

Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies—examined grossly and microscopically—that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks. PMID:23554812

SEIFEM 2017: from real life to an agreement on the use of granulocyte transfusions and colony-stimulating factors for prophylaxis and treatment of infectious complications in patients with hematologic malignant disorders.

PubMed

Busca, Alessandro; Cesaro, Simone; Teofili, Luciana; Delia, Mario; Cattaneo, Chiara; Criscuolo, Marianna; Marchesi, Francesco; Fracchiolla, Nicola Stefano; Valentini, Caterina Giovanna; Farina, Francesca; Di Blasi, Roberta; Prezioso, Lucia; Spolzino, Angelica; Candoni, Anna; Del Principe, Maria Ilaria; Verga, Luisa; Nosari, Annamaria; Aversa, Franco; Pagano, Livio

2018-02-01

The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 10 8 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.

Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wharam, M.D.; Kaizer, H.; Leventhal, B.G.

1980-02-01

Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologousmore » marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survived, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occurred in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.« less

[Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia].

PubMed

Ma, Xiao-li; Zhu, Ping; Wu, Min-yuan; Li, Zhi-gang; Hu, Ya-mei

2003-12-01

For the purpose of clarifying the influence of thiopurine methyltransferase (TPMT) gene single nucleotide polymorphisms (SNPs) on the efficacy of thiopurines and risk for its toxicity and therefore improving the safety and efficacy of thiopurines, the authors investigated TPMT genotype in acute leukemia in children who were intolerant to the treatment with 6-mercap topurine (6-MP). TPMT genotype was determined in an unrelated population of 250 Chinese healthy blood donors and 280 children with acute leukemia. TPMT genotyping assay was based on polymerase chain reaction (PCR), restriction digestion of PCR products, denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing in the TPMT * 2 (G238C), TPMT * 3A (G460A, A719G) and TPMT * 3C (A719G). There were 10 TPMT * 1/TPMT * 3C heterozygotes in 280 children. The frequency of the polymorphism was 3.6%. All the involved alleles were TPMT * 3C. Of the 160 children acute leukemia evaluated, 45 (26%) were intolerant to 6-MP. Presentations included hepatotoxicity and hematological toxicity. Six out of 45 children were heterozygous, while the other 39 were wild type homozygous. Before dosage adjustments for thiopurine, the hematologic toxicity and hepatotoxicity in TPMT heterozygous individuals occurred more frequently than in homozygous. Therefore, cases of TPMT heterozygotes experienced more missed doses of 6-MP. TPMT genotype is associated with tolerance in acute leukemia in children. The heterozygote individuals have low TPMT activity. Therefore the frequencies of hemtopoietic toxicity and hepatoxicity are high after using 6-MP. Detection of SNPs in the TPMT genes is useful in identifying children before administration of 6-MP.

Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using 90Yttrium and 177Lutetium labeled somatostatin analogs: toxicity, response and survival analysis

PubMed Central

Budiawan, Hendra; Salavati, Ali; Kulkarni, Harshad R; Baum, Richard P

2014-01-01

The overall survival rate of non-radioiodine avid differentiated (follicular, papillary, medullary) thyroid carcinoma is significantly lower than for patients with iodine-avid lesions. The purpose of this study was to evaluate toxicity and efficacy (response and survival) of peptide receptor radionuclide therapy (PRRT) in non-radioiodine-avid or radioiodine therapy refractory thyroid cancer patients. Sixteen non-radioiodine-avid and/or radioiodine therapy refractory thyroid cancer patients, including follicular thyroid carcinoma (n = 4), medullary thyroid carcinoma (n = 8), Hürthle cell thyroid carcinoma (n = 3), and mixed carcinoma (n = 1) were treated with PRRT by using 90Yttrium and/or 177Lutetium labeled somatostatin analogs. 68Ga somatostatin receptor PET/CT was used to determine the somatostatin receptor density in the residual tumor/metastatic lesions and to assess the treatment response. Hematological profiles and renal function were periodically examined after treatment. By using fractionated regimen, only mild, reversible hematological toxicity (grade 1) or nephrotoxicity (grade 1) were seen. Response assessment (using EORTC criteria) was performed in 11 patients treated with 2 or more (maximum 5) cycles of PRRT and showed disease stabilization in 4 (36.4%) patients. Two patients (18.2%) showed partial remission, in the remaining 5 patients (45.5%) disease remained progressive. Kaplan-Meier analysis resulted in a mean survival after the first PRRT of 4.2 years (95% CI, range 2.9-5.5) and median progression free survival of 25 months (inter-quartiles: 12-43). In non-radioiodine-avid/radioiodine therapy refractory thyroid cancer patients, PRRT is a promising therapeutic option with minimal toxicity, good response rate and excellent survival benefits. PMID:24380044

Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats

PubMed Central

Ghadirkhomi, Akram; Safaeian, Leila; Zolfaghari, Behzad; Agha Ghazvini, Mohammad Reza; Rezaei, Parisa

2016-01-01

Objective: Pinus eldarica (P. eldarica) is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. Materials and Methods: In the acute study, a single dose of extract (2000 mg/kg) was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day) of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. Results: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50) of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels. There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (p<0.05 and p<0.01, respectively) and in monocyte counts at the highest dose of the extract in both male and female rats (p<0.05). Mild inflammation was also found in histological examination of kidney and liver tissues at the highest dose of extract. Conclusion: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg. PMID:27761426

Acute and subchronic toxicity of 20  kHz and 60  kHz magnetic fields in rats

PubMed Central

Oshima, Atsushi; Shibuya, Kazumoto; Mitani, Takashi; Negishi, Tadashi

2015-01-01

Abstract Despite increasing use of intermediate frequency (IF) magnetic fields (MFs) in occupational and domestic settings, scientific evidence necessary for health risk assessments of IF MF is insufficient. Male and female Crl:CD(SD) rats (12 per sex per group) were exposed to 20 kHz, 0.20 mT(root mean square, rms) or 60 kHz, 0.10 mT(rms) sinusoidal MFs for 22 h day−1 for 14 days (acute) or 13 weeks (subchronic). Experiments were duplicated for each frequency to ensure outcome reproducibility, and examinations were blinded for quality assurance. All rats survived without significant clinical signs until the end of experiments. Some changes in body weight between the MF‐exposed and control groups were observed over the course of exposure, although the directions of the changes were inconsistent and not statistically significant after subchronic exposure. There were significant differences between MF‐exposed and control groups in some organ weights and parameters in hematology and clinical chemistry, but these were minor in magnitude and not repeated in duplicate experiments. Histopathological findings reflecting toxicity were sporadic. Frequencies of other findings were similar to historic data in this rat strain, and findings had no specific relationship to changes in organ weight or parameters of hematology and clinical chemistry in each animal. The changes observed throughout this study were considered biologically isolated and were attributable to chance associations rather than to MF exposure. The results, in particular the histopathological evidence, indicate an absence of toxicity in IF MF‐exposed rats and do not support the hypothesis that IF MF exposure produces significant toxicity. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd. PMID:25982482

Outcomes of induction chemotherapy followed by chemoradiation using intensity-modulated radiation therapy for esophageal adenocarcinoma.

PubMed

Gerber, N; Ilson, D H; Wu, A J; Janjigian, Y Y; Kelsen, D P; Zheng, J; Zhang, Z; Bains, M S; Rizk, N; Rusch, V W; Goodman, K A

2014-04-01

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease. © 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

Ameliorative role of nano-ceria against amine coated Ag-NP induced toxicity in Labeo rohita

NASA Astrophysics Data System (ADS)

Khan, Muhammad Saleem; Qureshi, Naureen Aziz; Jabeen, Farhat

2018-03-01

Silver nanoparticles (Ag-NPs) and its byproducts can spread pollution in aquatic habitat. Liver and gills are key target for toxicity. Oxidative stress, tissue alterations, and hemotoxicity are assumed to be associated with Ag-NPs in target animals. Cerium oxide nanoparticles (nano-ceria) show antioxidant potential in scavenging the free radicals generated in Ag-NP-induced oxidative stress. We determined ameliorated role of nano-ceria against Ag-NP-induced toxicity in fresh water Labeo rohita (L. rohita). Four groups were used in study including control, nano-ceria, Ag-NPs, and Ag-NPs + nano-ceria. Ag-NPs (30 mg l-1) and nano-ceria (50 µg kg-1) were given through water and prepared feed, respectively. The samples were taken after 28 days. Results demonstrated that pre-treatment of nano-ceria recovered L. rohita from Ag-NP-induced toxicity and oxidative stress. Nano-ceria pre-treatment actively mimics the activity of GST, GSH, CAT, and SOD. Furthermore, Ag-NPs' treatment caused severe inflammation and necrosis in hepatic parenchyma which leaded to congestion of blood in hepatic tissues. Accumulation of a yellow pigment in hepatic tissue was also seen due to necrosis of affected cells. In nano-ceria pre-treatment, there was no congestion in hepatic tissue. Vacuolization of cells and necrosis in some area was recorded in nano-ceria pre-treated group, but the gill and hepatic tissue showed improvement against Ag-NP-induced damage. Nano-ceria pre-treatment also improved hematological parameters in Ag-NP-treated fish. This study concluded that Ag-NP-induced toxicity in treated fish and pre-treatment of nano-ceria show ameliorative role.

Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

PubMed

Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

2012-04-10

Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

Safety and Tolerability of Panax ginseng Root Extract: A Randomized, Placebo-Controlled, Clinical Trial in Healthy Korean Volunteers

PubMed Central

Lee, Nam-Hun; Yoo, Sa-Ra; Kim, Hyeong-Geug; Cho, Jung-Hyo

2012-01-01

Abstract Objectives Panax ginseng has been extensively used as an adaptogen and is among the top 10 selling herbal supplements in the United States over the past decade. However, there have been few reports about the toxicity of P. ginseng in human studies. Given the lack of toxicological studies in human, this study investigated whether P. ginseng administration causes any noticeable toxic effects in healthy volunteers. Methods This study was designed as a randomized, double-blind, placebo-controlled, and parallel group trial in healthy volunteers. The subjects were required to be healthy, free from any significant disease, as assessed at screening by physical examination, medical history, and laboratory (hematological and biochemical) tests. Eligible subjects received P. ginseng extract (1 g/day or 2 g/day) or placebo over a 4-week period. Results Although mild adverse events, such as dyspepsia, hot flash, insomnia, and constipation, were reported in both P. ginseng and placebo group, no serious untoward reactions were reported following P. ginseng administration. Nonsignificant changes were observed in hematological and biochemical tests. Conclusions P. ginseng administration for 4 weeks was shown to be safe, tolerable, and free of any untoward toxic effect in healthy male and female volunteers. Future results from ongoing multicenter collaborative efforts to evaluate short- and long-term effects of P. ginseng may contribute to our current understanding of safety and tolerability of this herbal product. PMID:22909282

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

PubMed

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-09-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Subchronic toxicity evaluation of γ-aminobutyric acid (GABA) in rats.

PubMed

Takeshima, Kazuhito; Yamatsu, Atsushi; Yamashita, Yusuke; Watabe, Kazuya; Horie, Noriko; Masuda, Kazuyuki; Kim, Mujo

2014-06-01

γ-Aminobutyric acid (GABA) is an amino acid compound contained in vegetables such as tomatoes and also widely distributed in mammals. GABA acts as an inhibitory neurotransmitter and promotes parasympathetic activity to provide several beneficial effects, for instance, relaxation, anti-stress, and insomnia. GABA, produced via a fermentation process, has been available as a functional food ingredient. As part of a program to assess its safety, GABA was administered by oral gavage at doses of 500, 1250, and 2500mg/kg body weight to groups of 10 male and 10 female Sprague-Dawley rats for 13weeks. Treatment was not associated with the test substance-related mortality and appeared to be well tolerated. There were no toxicologically and statistically significant changes in urinalysis, hematology, clinical chemistry parameters, and in necropsy findings. A few statistically significant changes in food consumption and body weights were noted in the male groups while any significant changes were not noted in female groups. There was no effect of treatment on organ weights or on the results of the histopathological examinations. The results of toxicity evaluation support the safety use of GABA and the potential use as a functional food ingredient. Copyright © 2014 Elsevier Ltd. All rights reserved.

Targeting the Notch signaling pathway in autoimmune diseases.

PubMed

Ma, Daoxin; Zhu, Yuanchao; Ji, Chunyan; Hou, Ming

2010-05-01

The Notch signaling pathway regulates a variety of processes and has been linked to diverse effects. Aberrant Notch function is important in several disorders. Pre-clinical studies have suggested that inhibition of Notch is an attractive approach to treat hematologic and solid malignancies. Many patients with refractory autoimmune diseases respond poorly to therapy and have significant morbidity and the treatment is highly toxic, so more effective therapies for autoimmune diseases are being examined. The role of the Notch pathway and therapeutic strategies targeting it in many illnesses, especially autoimmune diseases. The Notch pathway has unique and attractive advantages for targeting. Targeting it has already been trialed in many experiments, which may show better efficacy and fewer side effects compared with classical drugs for the treatment. Targeting Notch might provide etiological rather than symptomatic treatment. Various methods targeting the Notch pathway have been under investigation. Rational targeting of the Notch signaling pathway in cancer and some autoimmune diseases has proven to be successful. Classical drugs for the treatment of autoimmune diseases are inefficient and toxic to some extent, and targeting the Notch pathway is a promising therapeutic concept. However, there are still many questions about targeting Notch in autoimmune diseases, and further investigation will be needed.

Translocations in epithelial cancers

PubMed Central

Chad Brenner, J.; Chinnaiyan, Arul M.

2009-01-01

Genomic translocations leading to the expression of chimeric transcripts characterize several hematologic, mesenchymal and epithelial malignancies. While several gene fusions have been linked to essential molecular events in hematologic malignancies, the identification and characterization of recurrent chimeric transcripts in epithelial cancers has been limited. However, the recent discovery of the recurrent gene fusions in prostate cancer has sparked a revitalization of the quest to identify novel rearrangements in epithelial malignancies. Here, the molecular mechanisms of gene fusions that drive several epithelial cancers and the recent technological advances that increase the speed and reliability of recurrent gene fusion discovery are explored. PMID:19406209

Assessment of in vivo systemic toxicity and biodistribution of iron-doped silica nanoshells.

PubMed

Mendez, Natalie; Liberman, Alexander; Corbeil, Jacqueline; Barback, Christopher; Viveros, Robert; Wang, James; Wang-Rodriguez, Jessica; Blair, Sarah L; Mattrey, Robert; Vera, David; Trogler, William; Kummel, Andrew C

2017-04-01

Silica nanoparticles are an emerging class of biomaterials which may be used as diagnostic and therapeutic tools for biomedical applications. In particular, hollow silica nanoshells are attractive due to their hollow core. Approximately 70% of a 500 nm nanoshell is hollow, therefore more particles can be administered on a mg/kg basis compared to solid nanoparticles. Additionally, their nanoporous shell permits influx/efflux of gases and small molecules. Since the size, shape, and composition of a nanoparticle can dramatically alter its toxicity and biodistribution, the toxicology of these nanomaterials was assessed. A single dose toxicity study was performed in vivo to assess the toxicity of 500 nm iron-doped silica nanoshells at clinically relevant doses of 10-20 mg/kg. This study showed that only a trace amount of silica was detected in the body 10 weeks post-administration. The hematology, biochemistry and pathological results show that the nanoshells exhibit no acute or chronic toxicity in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate.

PubMed

Jesus, Douglas Rossi; Barbosa, Lorena Neris; Prando, Thiago Bruno Lima; Martins, Leonardo Franco; Gasparotto, Francielli; Guedes, Karla Moraes Rocha; Dragunski, Douglas Cardoso; Lourenço, Emerson Luiz Botelho; Dalsenter, Paulo Roberto; Gasparotto Junior, Arquimedes

2015-01-01

The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

A subchronic toxicity study of elemental Nano-Se in Sprague-Dawley rats.

PubMed

Jia, X; Li, N; Chen, J

2005-03-11

The subchronic toxicity of Nano-Se was compared with selenite and high-selenium protein in rats. Groups of Sprague-Dawley rats (12 males and 12 females per group) were fed diets containing Nano-Se, selenite and high-selenium protein at concentrations of 0, 2, 3, 4 and 5 ppm Se, respectively, for 13 weeks. Clinical observations were made and body weight and food consumption were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry determination. Histopathological examination was performed on selected tissues. At the two higher doses (4 and 5 ppm Se), significant abnormal changes were found in body weight, hematology, clinical chemistry, relative organ weights and histopathology parameters. However, the toxicity was more pronounced in the selenite and high-selenium protein groups than the Nano-Se group. At the dose of 3 ppm Se, significant growth inhibition and degeneration of liver cells were found in the selenite and high-selenium protein groups. No changes attributable to administration of Nano-Se at the dose of 3 ppm Se were found. Taken together, the no-observed-adverse-effect level (NOAEL) of Nano-Se in male and female rats was considered to be 3 ppm Se, equivalent to 0.22 mg/kg bw/day for males and 0.33 mg/kg bw/day for females. On the other hand, the NOAELs of selenite and high-selenium protein in males and females were considered to be 2 ppm Se, equivalent to 0.14 mg/kg bw/day for males and 0.20 mg/kg bw/day for females. In addition, studies have shown that Nano-Se has a similar bioavailability in rat, and much less acute toxicity in mice compared with selenite. In conclusion, Nano-Se is less toxic than selenite and high-selenium protein in the 13-week rat study.

Two cases of paralitic ileus in onco-hematologic patients

PubMed Central

Carraro, Francesca; Rivetti, Elisa; Romano, Erica; Fagioli, Franca

2012-01-01

Paralytic ileus is a severe complication resulting from a variety of disorders. It occurs most commonly in patients with serious underlying medical or surgical conditions. Prompt diagnosis and appropriate management may improve the outcome. We describe 2 cases of onco-hematologic patients who presented this complication after intensive chemotherapy. PMID:22690309

Interspecies variation in the susceptibility of adult Pacific salmon to toxic urban stormwater runoff.

PubMed

McIntyre, Jenifer K; Lundin, Jessica I; Cameron, James R; Chow, Michelle I; Davis, Jay W; Incardona, John P; Scholz, Nathaniel L

2018-07-01

Adult coho salmon (Oncorhynchus kisutch) prematurely die when they return from the ocean to spawn in urban watersheds throughout northwestern North America. The available evidence suggests the annual mortality events are caused by toxic stormwater runoff. The underlying pathophysiology of the urban spawner mortality syndrome is not known, and it is unclear whether closely related species of Pacific salmon are similarly at risk. The present study co-exposed adult coho and chum (O. keta) salmon to runoff from a high traffic volume urban arterial roadway. The spawners were monitored for the familiar symptoms of the mortality syndrome, including surface swimming, loss of orientation, and loss of equilibrium. Moreover, the hematology of both species was profiled by measuring arterial pH, blood gases, lactate, plasma electrolytes, hematocrit, and glucose. Adult coho developed behavioral symptoms within a few hours of exposure to stormwater. Various measured hematological parameters were significantly altered compared to coho controls, indicating a blood acidosis and ionoregulatory disturbance. By contrast, runoff-exposed chum spawners showed essentially no indications of the mortality syndrome, and measured blood hematological parameters were similar to unexposed chum controls. We conclude that contaminant(s) in urban runoff are the likely cause of the disruption of ion balance and pH in coho but not chum salmon. Among the thousands of chemicals in stormwater, future forensic analyses should focus on the gill or cardiovascular system of coho salmon. Because of their distinctive sensitivity to urban runoff, adult coho remain an important vertebrate indicator species for degraded water quality in freshwater habitats under pressure from human population growth and urbanization. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ameliorating Role of Lycopene, Tomato Puree, and Spirulina + Tomato Puree on the Hematology of Fluoride-Exposed Swiss Albino Mice.

PubMed

Sharma, Shweta; Parashar, Puneet; Sharma, Subhasini; Sharma, Kanta Prasad

2018-01-16

Plant species rich in antioxidants (vitamins, flavonoids, lignans, and carotenoids) have been explored for complementary therapy of chronic diseases (cancers, coronary heart disease) and mitigation of pollutant toxicity. This article investigates their ameliorative role on selective hematological and serum biochemical parameters in fluoride-exposed (190 mg/kg body weight) Swiss albino mice pretreated with the antioxidant-rich diet supplements tomato puree (with and without peels), spirulina (cyanobacteria), and lycopene (present in tomato) for 45 days prior to entry into experimental protocol. Compared with standard feed control, diet-modulated controls had more hairy and lustrous white fur, hemodilution, increase in platelet counts (2- to 5-fold), red blood cell (RBC) size (11%-14%), mean corpuscular hemoglobin (Hb) concentration (MCHC; 5%-14%), and serum albumin (23%-27%). Fluoride-exposed mice reared on standard feed had less hairy, pale white, lusterless fur and black nails, reduction in RBC and white blood cell (WBC) counts and Hb content, and morphological abnormalities in RBCs (poikilocytosis). By contrast, fur quality of fluoride-treated diet-modulated groups was similar to standard feed control; counts and morphology of their RBCs and Hb content similar to the respective controls, and increase in WBC counts greater than controls. In comparison to the fluoride-treated standard feed group, platelet counts were higher in the treated mice of the diet-modulated groups. This study thus revealed the hemoprotective role of diet supplements in fluoride-treated mice. Considering the prevalence of fluoride-induced chronic toxicity in developing countries, our findings have relevance in minimizing hematological disorders among people residing in the fluoride-affected areas, because indigenously cultivated low-price tomato fruits are easily available for consumption.

Virus-Specific T Cells for the Immunocompromised Patient

PubMed Central

Houghtelin, Amy; Bollard, Catherine M.

2017-01-01

While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs) is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST), which are not only effective but also confer protection in 70–90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy in vivo. PMID:29075259

Virus-Specific T Cells for the Immunocompromised Patient.

PubMed

Houghtelin, Amy; Bollard, Catherine M

2017-01-01

While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs) is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST), which are not only effective but also confer protection in 70-90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy in vivo .

A prospective picture collection study for a grading atlas of radiation dermatitis for clinical trials in head-and-neck cancer patients

PubMed Central

Zenda, Sadamoto; Ota, Yosuke; Tachibana, Hiroyuki; Ogawa, Hirofumi; Ishii, Shinobu; Hashiguchi, Chikako; Akimoto, Tetsuo; Ohe, Yuichiro; Uchitomi, Yosuke

2016-01-01

Radiation dermatitis is one of the most common acute toxicities of both radiotherapy and chemoradiotherapy. Many clinical trials have evaluated the level of toxicity using the Common Terminology Criteria for Adverse Events ver. 4.03. This criterion accounts for severity in a single sentence only, and no visual classification guide has been available. Thus, there is a risk of subjective interpretation by the individual investigator. This contrasts with the situation with hematologic toxicities, which can be interpreted objectively. The aim of this prospective picture collection study was to develop a grading tool for use in establishing the severity of radiation dermatitis in clinical trials. A total of 118 patients who were scheduled to receive definitive or postoperative radiotherapy or chemoradiotherapy were enrolled from the four participating cancer centers. All researchers in our group used the same model of camera under the same shooting conditions to maintain consistent photographic quality. In all, 1600 photographs were collected. Of these, 100 photographs qualified for the first round of selection and were then graded by six experts, basically in accordance with the CTCAE ver. 4.03 (JCOG ver. in Japanese). After further study, 38 photographs were selected as representing typical models for Grade 1–4 radiation dermatitis; the radiation dermatitis grading atlas was produced from these photographs. The atlas will play a major role in ensuring that the dermatitis rating system is consistent between the institutions participating in trials. We hope that this will contribute to improving the quality of clinical trials, and also to improving the level of routine clinical practice. PMID:26850926

Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.

PubMed

Nishijima, Tomohiro F; Shachar, Shlomit S; Nyrop, Kirsten A; Muss, Hyman B

2017-04-01

Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy. PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors. PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer. © AlphaMed Press 2017.

Safety and Tolerability of PD‐1/PD‐L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta‐Analysis

PubMed Central

Shachar, Shlomit S.; Nyrop, Kirsten A.; Muss, Hyman B.

2017-01-01

Abstract Background. Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor‐1 (PD‐1) inhibitors nivolumab and pembrolizumab and the programmed death‐ligand 1 (PD‐L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta‐analysis to compare safety and tolerability between PD‐1/PD‐L1 inhibitors and chemotherapy. Methods. PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single‐agent U.S. Food and Drug Administration–approved PD‐1/PD‐L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all‐grade (1–4) or high‐grade (3–4) adverse events (AEs), all‐ or high‐grade treatment‐related symptoms, hematologic toxicities and immune‐related AEs, treatment discontinuation due to toxicities, or treatment‐related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. Results. A total of 3,450 patients from 7 RCTs were included in the meta‐analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non‐small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD‐1/PD‐L1 inhibitors had a significantly lower risk of all‐ and high‐grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all‐grade anorexia, nausea, and constipation, any all‐ and high‐grade AEs, and treatment discontinuation. There was an increased risk of all‐grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all‐ and high‐grade pneumonitis with PD1/PD‐L1 inhibitors. Conclusion. PD‐1/PD‐L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD‐1/PD‐L1 inhibitors. Implications for Practice. We conducted a systematic review and meta‐analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors and chemotherapy. PD1/PD‐L1 inhibitors were associated with a lower risk of treatment‐related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune‐related adverse events (AEs). Summary toxicity endpoints favor PD1/PD‐L1 inhibitors (any all‐ and high‐grade AEs and treatment discontinuation). PD1/PD‐L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well‐balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer. PMID:28275115

Pemetrexed safety and pharmacokinetics in patients with third-space fluid.

PubMed

Dickgreber, Nicolas J; Sorensen, Jens Benn; Paz-Ares, Luis G; Schytte, Tine Kjestrup; Latz, Jane E; Schneck, Karen B; Yuan, Zheng; Sanchez-Torres, José Miguel

2010-05-15

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary. Copyright (c) 2010 AACR.

Irradiation of FDG-PET–Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rose, Brent S., E-mail: bsrose@lroc.harvard.edu; Jee, Kyung-Wook; Niemierko, Andrzej

Purpose: Irradiation of pelvic bone marrow (BM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. We hypothesized that irradiation of hematologically active bone marrow (ABM) subregions defined by fluorodeoxyglucose (FDG) positron emission tomography (PET) is a principal cause of radiation-associated HT. Methods and Materials: The cohort included 45 patients with nonmetastatic anal cancer who underwent FDG-PET imaging prior to definitive chemoradiation with mitomycin-C and 5-fluorouracil. Total bone marrow (TBM) was defined as the external contour of the pelvic bones from the top of lumbar 5 (L5) to the bottom of the ischial tuberosity. Standardizedmore » uptake values (SUV) for all voxels within the TBM were quantified and normalized by comparison to normal liver SUV. Subvolumes of the TBM that exhibited the highest and lowest 50% of the SUVs were designated ABM{sub 50} and IBM{sub 50}, respectively. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2 weeks of completion of treatment. Multivariate linear modeling was used to analyze the correlation between the equivalent uniform doses (EUD) with an a value of 0.5, 1 (equivalent to mean dose), 3, 7, and 12 to the BM structures and the ANC. Results: Mean ± SD ANC nadir was 0.77 × 10{sup 9}/L (±0.66 × 10{sup 9}/L). Grades 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. The EUD a parameter of 0.5 was optimal for all BM models indicating high radiation sensitivity. EUD of TBM and ABM{sub 50} and IBM{sub 50} were all significantly associated with ANC nadir. However, model performance for ABM{sub 50} was not superior to that of the TBM and IBM{sub 50} models. Conclusions: Irradiation of pelvic BM was associated with HT. However, FDG-PET–defined ABM models failed to improve model performance compared to the TBM model.« less

Feasibility of Preoperative Chemotherapy With or Without Radiation Therapy in Localized Soft Tissue Sarcomas of Limbs and Superficial Trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: Three Versus Five Cycles of Full-Dose Epirubicin Plus Ifosfamide.

PubMed

Palassini, Elena; Ferrari, Stefano; Verderio, Paolo; De Paoli, Antonino; Martin Broto, Javier; Quagliuolo, Vittorio; Comandone, Alessandro; Sangalli, Claudia; Palmerini, Emanuela; Lopez-Pousa, Antonio; De Sanctis, Rita; Bottelli, Stefano; Libertini, Michela; Picci, Piero; Casali, Paolo G; Gronchi, Alessandro

2015-11-01

We report on feasibility of preoperative chemotherapy with or without radiation therapy (RT) in the context of a phase III randomized clinical trial involving localized, high-risk, soft tissue sarcomas. Of 321 eligible patients, 161 were randomly assigned to three preoperative cycles of epirubicin 120 mg/m(2) plus ifosfamide 9 g/m(2), and 160 were randomly assigned to three preoperative plus two postoperative cycles. Among them, 303 patients were included in this analysis; 169 were male and 134 were female, with a median age of 48 years (range, 15 to 79 years). One hundred fifty-two patients received concurrent RT preoperatively at a total dose of 44 to 50 Gy. Preoperative chemotherapy-related hematologic toxicity and early postoperative complications were reported. The influence of RT, age, and sex on hematologic grade 3 or 4 toxicities and wound complications was analyzed. Chemotherapeutic dose intensity (DI) was analyzed. Among the patients, 61.4%, 22.4%, and 23.8% experienced, grade 4 leucopenia, grade 3 or 4 anemia, and grade 3 or 4 thrombocytopenia, respectively. Respective rates were 66.4%, 24.3%, and 31.6% when RT was added preoperatively, and 56.3%, 20.5%, and 15.9% when preoperative chemotherapy was administered alone. Patient age affected grade 3 or 4 thrombocytopenia. Grade 4 leucopenia and grade 3 or 4 anemia presented 2.5 times more frequently in female patients than in male patients. Wound complications were observed in 13.5% of patients: 17% with preoperative RT and 10% without. Chemotherapeutic DI was greater than 90%, even in patients receiving preoperative RT and in patients age 65 years or older. This preoperative chemotherapy is feasible and can also be proposed for selected elderly patients. Grade 3 or 4 hematologic toxicity was common, but DI was excellent. Concurrent preoperative RT is safe, although an increased rate of grade 4 thrombocytopenia and limited increase in wound complications may be observed. © 2015 by American Society of Clinical Oncology.

Experimental lead toxicosis in ponies: comparison of the effects of smelter effluent-contaminated hay and lead acetate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burrows, G.E.; Borchard, R.E.

1982-12-01

Grass hay produced in the Coeur d'Alene River Basin of northern Idaho was fed to a group of 4 ponies. The hay contained Pb in concentration of 423 +/- 82 mg/kg and Cd in concentration of 10.8 +/- 1.4 mg/kg, resulting in daily exposures of the ponies to approximately 7.4 mg of Pb/kg and 0.19 mg of Cd/kg/day. The results in this group of ponies were compared with those from a group fed noncontaminated grass hay and given a daily dose of 10 mg of Pb/kg of body weight, in the form of lead acetate. Clinical toxicologic signs, hematologic changes,more » and blood and tissue Pb concentrations were similar in the 2 groups. However, the severity of the disease process appeared to be greater in the ponies fed the Pb- and Cd-contaminated hay. This was shown clearly by the shorter interval between onset of clinical changes and death in the ponies fed contaminated hay. The possibility of multiple heavy metal effects is discussed. Clinical toxicologic signs observed include incoordination, labial paresis, pharyngeal paresis, CNS depression, anorexia, and body weight loss. Anemia or marginal anemia was common and was often accompanied by the appearance of nucleated RBC and Howell-Jolly bodies in peripheral blood. Neither the hematologic response nor the blood Pb concentrations were reflective of the severity of poisoning, although blood Pb concentrations were greater than 0.35 micrograms/ml once clinical signs of toxicity were observed. Liver, kidney, spleen, brain, and bone Pb concentrations and liver, kidney, and brain Cd concentrations were increased in both the ponies fed contaminated hay and the ponies given lead acetate.« less

Safety of Pochonia chlamydosporia var catenulata in acute oral and dermal toxicity/pathogenicity evaluations in rats and rabbits.

PubMed

García, Liseth; Bulnes, Carlos; Melchor, Gleiby; Vega, Ernesto; Ileana, Miranda; de Oca, Nivian Montes; Hidalgo, Leopoldo; Marrero, Eva

2004-10-01

The nematophagous fungus, Pochonia chlamydosporia var. catenulata (Kamyschlco ex Barron & Onions) Zare & W-Gams, was investigated as a potential biocontrol agent in integrated pest management strategy for Meloidogyne incognita (Kofoid and White) Chitwood in vegetable crops in Cuba. An acute oral and dermal toxicity/patogenicity study was performed to determine the safety of this fungus in non-target organisms. In the first study, a 1-dose level of 5 x 10(8) units of the microbial pest control agent/treated rat was used. Mortality or clinical signs were not evident and no adverse effects on body weight, hematology, microbiology and gross or microscopic pathology were observed. Food and water consumption was not significantly different between control and treated groups. In the acute dermal toxicity study, there was neither mortality nor clinical signs of toxicity, and no toxic effects in gross and microscopic pathology were detected. Thus, Pochonia chlamydosporia var. catenulate (Vcc-108, IMI SD 187), administered oral and dermally to rats and rabbits respectively, was safe in toxicity/pathogenicity studies.

Palifermin in the management of mucositis in hematological malignancies: current evidences and future perspectives.

PubMed

Niscola, Pasquale; Scaramucci, Laura; Giovannini, Marco; Ales, Micaela; Bondanini, Francesco; Cupelli, Luca; Dentamaro, Teresa; Lamanda, Michela; Natale, Giuseppina; Palumbo, Roberto; Romani, Claudio; Tendas, Andrea; Tolu, Barbara; Violo, Leano; de Fabritiis, Paolo

2009-10-01

In the management of hematological malignancies, chemotherapy-induced mucositis is an increasingly recognized problem, leading to potentially severe clinical complications, treatment delays, increased costs and impairment of patient's quality of life. Many forms of cytotoxic treatments given in this setting may induce several degrees of mucositis. In particular, conditioning therapy with hematopoietic stem cell transplantation (HSCT) induces a disruption of the mucosal barrier function throughout the entire gastrointestinal tract facilitating the spreading of bacteria and endotoxin with subsequent increased risk of septicemia and, in the allogeneic setting, a worsening of Graft Versus Host Disease (GVHD). To review the role of palifermin and of other existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology in the setting of hematological malignancies. We searched for palifermin and mucositis of any region of the gastrointestinal tract using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are highly required. In this regard, palifermin (recombinant human keratinocyte growth factor) has been demonstrated to reduce the severity and the duration of oral mucositis and to significantly improve several treatment outcomes in patients submitted to autologous HSCT; data are insufficient to recommend its use in the non-autologous HSCT settings, although interesting properties of this agent deserves other investigations in order to explore other possible indications.

Reference ranges of hematology and lymphocyte subsets in healthy Korean native cattle (Hanwoo) and Holstein dairy cattle.

PubMed

Kim, Yun-Mi; Lee, Jin-A; Jung, Bock-Gie; Kim, Tae-Hoon; Lee, Bong-Joo; Suh, Guk-Hyun

2016-06-01

There are no accurate reference ranges for hematology parameters and lymphocyte subsets in Korean native beef cattle (Hanwoo). This study was performed to establish reliable reference ranges of hematology and lymphocyte subsets using a large number of Hanwoo cattle (n = 350) and to compare differences between Hanwoo and Holstein dairy cattle (n = 334). Additionally, age-related changes in lymphocyte subsets were studied. Bovine leukocyte subpopulation analysis was performed using mono or dual color flow cytometry. The leukocyte subpopulations investigated in healthy cattle included: CD2(+) cells, sIgM(+) cells, MHC class II(+) cells, CD3(+) CD4(+) cells, CD3(+) CD8(+) cells, and WC1(+) cells. Although Hanwoo and Holstein cattle are the same species, results showed several differences in hematology and lymphocyte subsets between Hanwoo and Holstein cattle. This study is the first report to establish reference ranges of hematology and lymphocyte subsets in adult Hanwoo cattle. © 2015 Japanese Society of Animal Science.

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model.

PubMed

Gnann, Laís Angelo; Castro, Rafael Ferreira; Azzalis, Ligia Ajaime; Feder, David; Perazzo, Fabio Ferreira; Pereira, Edimar Cristiano; Rosa, Paulo César Pires; Junqueira, Virginia Berlanga Campos; Rocha, Katya Cristina; Machado, Carlos D' Aparecida; Paschoal, Francisco Camargo; de Abreu, Luiz Carlos; Valenti, Vitor Engrácia; Fonseca, Fernando Luiz Affonso

2013-10-29

Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity.

Acute and sub-chronic toxicity studies of honokiol microemulsion.

PubMed

Zhang, Qianqian; Li, Jianguo; Zhang, Wei; An, Quan; Wen, Jianhua; Wang, Aiping; Jin, Hongtao; Chen, Shizhong

2015-04-01

The purpose of this study was to investigate the acute and sub-chronic toxicity of honokiol microemulsion. In the acute toxicity tests, the mice were intravenously injected graded doses of honokiol microemulsion and were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were injected honokiol microemulsion at doses of 100, 500, 2500 μg/kg body weight (BW) for 30 days. After 30 days treatment and 14 days recovery, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD50) was 50.5mg/kg body weight in mice. In the sub-chronic toxicity tests, the non-toxic reaction dose was 500 μg/kg body weight. In each treatment group, degeneration or/and necrosis in vascular endothelial cells and structure change of vessel wall can be observed in the injection site (cauda vein) of a few animals while there were no changes in the vessels of other organs. The overall findings of this study indicate that the honokiol microemulsion is non-toxic up to 500 μg/kg body weight, and it has irritation to the vascular of the injection site which should be paid attention to in clinical medication. Copyright © 2015. Published by Elsevier Inc.

Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia.

PubMed

Feben, Candice; Kromberg, Jennifer; Wainwright, Rosalind; Stones, David; Poole, Janet; Haw, Tabitha; Krause, Amanda

2015-03-01

Fanconi anemia (FA) is a rare disorder of DNA repair, associated with various somatic abnormalities but characterized by hematological disease that manifests as bone marrow aplasia and malignancy. The mainstay of treatment, in developed nations, is hematopoietic stem cell transplantation (HSCT) with subsequent surveillance for solid organ and non-hematological malignancies. In South Africa, FA in the Black population is caused by a homozygous deletion mutation in the FANCG gene in more than 80% of cases. Many affected patients are not diagnosed until late in the disease course when severe cytopenia and bone marrow aplasia are already present. Most patients are not eligible for HSCT at this late stage of the disease, even when it is available in the state health care system. In this study, the hematological presentation and disease progression in 30 Black South African patients with FA, confirmed to have the FANCG founder mutation, were evaluated and compared to those described in other FA cohorts. Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype. Further, the incidence of myelodysplastic syndrome is similar to that which has been previously described in other FA cohorts. Although severe cytopenia at presentation may be predicted by a higher number of somatic anomalies, the recognition of the physical FA phenotype in Black South African patients is challenging and may not be useful in expediting referral of suspected FA patients for tertiary level investigations and care. Given the late but severe hematological presentation of FA in Black South African patients, an investigative strategy is needed for earlier recognition of affected individuals to allow for possible HSCT and management of bone marrow disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non-Small-Cell Lung Cancer.

PubMed

Sjøblom, Bjørg; Benth, Jūratė Šaltytė; Grønberg, Bjørn H; Baracos, Vickie E; Sawyer, Michael B; Fløtten, Øystein; Hjermstad, Marianne J; Aass, Nina; Jordhøy, Marit

2017-03-01

Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) enrolled onto randomized trials comparing first-line carboplatin-doublets. Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m 2 , gemcitabine 1000 mg/m 2 , or vinorelbine 60 mg/m 2 . LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1. Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed ∼3-fold range: gemcitabine 38.0 (22.5-61.7) mg/kg LBM, pemetrexed 19.1 (8.1-27.9) mg/kg LBM, and vinorelbine 2.4 (1.4-3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models (P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01-1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95-0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21-3.10) and halved (OR = 0.52; 95% CI, 0.32-0.83), respectively. Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography-defined LBM may provide a future basis for better dose individualization. Copyright © 2016 Elsevier Inc. All rights reserved.

Hematologic and plasma biochemical changes associated with fenbendazole administration in Hermann's tortoises (testudo hermanni).

PubMed

Neiffer, Donald L; Lydick, Dianna; Burks, Kyle; Doherty, Donna

2005-12-01

Toxicosis associated with benzimidazole anthelmintics has been reported with increasing frequency in zoologic collections. Clinical signs, clinicopathologic abnormalities, and gross and histologic lesions are primarily the result of damage to the gastrointestinal and hematopoietic systems. Profound leukopenia, especially granulocytopenia, is the most common and severe clinicopathologic change associated with benzimidazole administration. Death usually occurs from overwhelming systemic bacterial and/or fungal infections secondary to severe immunosuppression. In this 125-day study, six male Hermann's tortoises (Testudo hermanni) were treated orally with two 5-day courses of fenbendazole 2 wk apart at a dosage of 50 mg/kg. Serial blood samples were used to assess hematologic and plasma biochemical changes before, during, and following the treatment period. Although the tortoises remained healthy, blood sampling indicated an extended heteropenia with transient hypoglycemia, hyperuricemia, hyperphosphatemia, and equivocal hyperproteinemia/hyperglobulinemia, which were considered to be in response to fenbendazole administration. Changes in several other clinicopathologic parameters appeared to correlate with fenbendazole administration. The hematologic and biochemical changes seen in the healthy animals in this study should be considered when treating compromised tortoises with fenbendazole. Hematologic and plasma biochemical status of tortoises/reptiles should be determined before treatment and monitored during the treatment period. The risk of mortality of an individual from nematode infection should be assessed relative to the potential for metabolic alteration and secondary septicemia following damage to hematopoietic and gastrointestinal systems by fenbendazole.

[Toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (4). 6-month repeated dose intravenous toxicity study in rats with 1-month recovery test].

PubMed

Yamaguchi, K; Aze, Y; Shimizu, K; Shichino, Y; Oku, H; Mori, H; Shinomiya, K; Ueda, H; Suzuki, Y; Oida, H; Nishibata, K; Tanaka, M; Yanagizawa, Y; Nanba, T; Nishiyama, K; Yonezawa, H; Fujita, T

1998-07-01

A 6-month repeated dose toxicity study with 1-month recovery test of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley (SD) rats. The rats of both sexes were administered ONO-5046.Na intravenously at a daily dose of 0 (vehicle control), 18.75, 37.5 or 75 mg/kg. ONO-5046.Na did not affect clinical signs, body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology at any dose. These results indicate that the NOAEL of ONO-5046.Na in rats is 75 mg/kg/day for both sexes in this study.

Consideration for solar system exploration - A system to Mars. [biomedical, environmental, and psychological factors

NASA Technical Reports Server (NTRS)

Nicogossian, Arnauld E.; Garshnek, Victoria

1989-01-01

Biomedical issues related to a manned mission to Mars are reviewed. Consideration is given to cardiovascular deconditioning, hematological and immunological changes, bone and muscle changes, nutritional issues, and the development of physiological countermeasures. Environmental issues are discussed, including radiation hazards, toxic chemical exposure, and the cabin environment. Also, human factors, performance and behavior, medical screening of the crew, disease prediction, and health maintenance are examined.

The Metabolism of Tetralin in Fischer 344 Rats

DTIC Science & Technology

1986-04-01

evaluated petroleum and shale-derived JP-5, a jet fuel composed of aliphatic and aromatic hydrocarbons with the majority of the straight-chain...much like gasoline. JP-8 is a mixture of hydrocarbons of intermediate boiling point and volatility and is similar to the civilian jet fuel , A-1. DFM...toxicity of conventional versus shale-derived JP-5 jet fuel : Light microscopy, hematologic, and serum chemistry studies. Toxicol Appl Pharmacol, 57

Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma.

PubMed

Broccoli, Alessandro; Casadei, Beatrice; Morigi, Alice; Sottotetti, Federico; Gotti, Manuel; Spina, Michele; Volpetti, Stefano; Ferrero, Simone; Spina, Francesco; Pisani, Francesco; Merli, Michele; Visco, Carlo; Paolini, Rossella; Zilioli, Vittorio Ruggero; Baldini, Luca; Di Renzo, Nicola; Tosi, Patrizia; Cascavilla, Nicola; Molica, Stefano; Ilariucci, Fiorella; Rigolin, Gian Matteo; D'Alò, Francesco; Vanazzi, Anna; Santambrogio, Elisa; Marasca, Roberto; Mastrullo, Lucia; Castellino, Claudia; Desabbata, Giovanni; Scortechini, Ilaria; Trentin, Livio; Morello, Lucia; Argnani, Lisa; Zinzani, Pier Luigi

2018-05-04

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.

Ecotoxicological impacts of clofibric acid and diclofenac in common carp (Cyprinus carpio) fingerlings: hematological, biochemical, ionoregulatory and enzymological responses.

PubMed

Saravanan, Manoharan; Karthika, Subramanian; Malarvizhi, Annamalai; Ramesh, Mathan

2011-11-15

Investigation on the toxic effects of pharmaceutical drugs namely clofibric acid (CA) and diclofenac (DCF) were studied in a common carp Cyprinus carpio at different concentrations such as 1, 10 and 100 μg L(-1) for a short-term period of 96 h under static bioassay method. At all concentrations, red blood cell (RBC), plasma sodium (Na(+)), potassium (K(+)), and glutamate oxaloacetate transaminase (GOT) levels were decreased in fish treated with CA and DCF. Contrastingly, white blood cell (WBC), plasma glucose, protein, lactate dehydrogenase (LDH) and gill Na(+)/K(+)-ATPase level were increased. However, a mixed trend was observed in hemoglobin (Hb), hematocrit (Hct), plasma chloride (Cl(-)), mean cellular volume (MCV), mean cellular hemoglobin (MCH), mean cellular hemoglobin concentration (MCHC) and glutamate pyruvate transaminase (GPT) levels. There was a significant (P<0.01 and P<0.05) change in all parameters measured in fish exposed to different concentrations of CA and DCF. In summary, the alterations in hematological, biochemical, ionoregulatory and enzymological parameters can be used as biomarkers in monitoring the toxicity of CA and DCF in aquatic environment. However, more detailed studies on using of specific biomarkers to monitor the human pharmaceuticals are needed. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of hesperidin on formaldehyde-induced toxicity in pregnant rats

PubMed Central

Merzoug, Sameha; Toumi, Mohamed Lamine

2017-01-01

This experimental study aimed to investigate the protective effect of a bioflavonoid, hesperidin (HP), on formaldehyde (FA)-related pathophysiological and behavioral outcomes in pregnant rats and developmental aspects in their offspring. Female Wistar rats were subjected to perigestational exposure to FA (2 mg/kg/day per os) with a concomitant treatment with HP (50 mg/kg/day per os). Pregnant rats were weighed throughout gestation and tested in two behavioral paradigms (elevated plus-maze and open field) at gestational days (GD) 1, 10 and 19 to evaluate the anxiety-like behavior and locomotive alterations. Another subset of rats was decapitated at GD19 to determine the hematological profile along with cortisol, 17β-estradiol, and progesterone plasma levels. Reproductive and fetal measures and observations were also performed to check for developmental deformities. Significant body weight loss, hemato-immune decline, hormonal changes, anxiety and lethargy signs, locomotor disabilities, reproductive failure and fetal weight decrease were observed in FA-exposed rats. Treatment with HP alleviated the reproductive and fetal weight defects. Its behavioral benefits were only seen at GD1 and 10. This flavanone ameliorated some hematological parameters, decreased cortisol levels and increased 17β-estradiol rates. A potential preventive impact of HP was found against FA toxicity in pregnant rats. PMID:28507483

A 90-day subchronic toxicity study with sodium formononetin-3'-sulphonate (Sul-F) delivered to dogs via intravenous administration.

PubMed

Li, Chunmei; Li, Guisheng; Gao, Yonglin; Sun, Chengfeng; Wang, Xiaoyan

2016-06-01

Sodium formononetin-3'-sulphonate (Sul-F) is a water-soluble derivate of formononetin, and an increasing number of studies have shown that Sul-F not only possesses favorable water solubility but also exhibits good lipid-lowering and bioactivities. In the current study, the toxicity of Sul-F was evaluated in dogs after 90-day intravenous infusion. Dogs were treated with Sul-F at dose of 0, 33.3, 100, and 300 mg/kg, and observed for 90-day followed by 28-day recovery period. Weekly measurement of body weight, temperature and food consumption were conducted. Ophthalmoscopy, ECG examination, urinalysis, serum biochemistry and hematology examination were performed at pre-test, on days 45 and 90, and following by 28-day recovery period. Histological examination was performed on day 90 and 28-day recovery period. No mortality, ophthalmic abnormalities or treatment-related findings in body weight, clinical chemistry, hematology, and histopathological examination were detected. However, a white crystal (non-metabolic Sul-F), transient vomiting and recoverable vascular stimulation were observed in 300 mg/kg/day Sul-F treated dogs. Under the conditions, the no-observed-adverse-effect-level (NOAEL) for Sul-F was 100 mg/kg in dogs. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in swine.

PubMed

Dagenais, Simon; Wooley, James; Hite, Mark; Green, Robert; Mayer, John

2009-01-01

Prolotherapy is one of the many treatments available for chronic musculoskeletal disorders. A commonly used drug contains dextrose 12.5%, glycerin 12.5%, phenol 1.0%, and lidocaine hydrochloride 0.25% in aqueous solution (recently termed Proliferol). For chronic low back pain, this is injected into lumbosacral ligaments to stimulate connective tissue repair. Despite generally positive clinical results, the toxicity of this drug is not well characterized and was assessed in 48 (24 male, 24 female) Yucatan miniature swine randomly assigned to low (1x), medium (5x), or high (10x) dose or saline placebo. Outcomes included clinical observations, clinical chemistry, hematology, coagulation, urinalysis, toxicokinetics, and full gross and microscopic histopathology after 24 hours or 14 days. Findings attributable to Proliferol after 24 hours included dose-response elevations in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase, which returned to normal after 14 days. There were no remarkable findings in hematology, coagulation, or urinalysis. Urine concentrations of lidocaine and phenol both peaked after 8 hours. Histopathology findings after 24 hours included hemorrhage, inflammation, necrosis, and vascular changes in the ligaments and adjacent soft tissues at the sites of injection. After 14 days, there was evidence of repair under way, with fibrosis and skeletal muscle regeneration at the injection sites.

Acute and subacute toxicity and chemical constituents of the hydroethanolic extract of Verbena litoralis Kunth.

PubMed

de Lima, Rachel; Guex, Camille Gaube; da Silva, Andreia Regina Haas; Lhamas, Cibele Lima; Dos Santos Moreira, Karen Luise; Casoti, Rosana; Dornelles, Rafaela Castro; Marques da Rocha, Maria Izabel Ugalde; da Veiga, Marcelo Leite; de Freitas Bauermann, Liliane; Manfron, Melânia Palermo

2018-05-14

Verbena litoralis Kunth is a native species of South America, popularly known as gervãozinho-do-campo ou erva-de-pai-caetano. It is used in gastrointestinal disorders, as detoxifying the organism, antifebrile properties and amidaglitis. To identify the chemical constituents of the hydroethanolic extract obtained from the aerial parts of V. litoralis and to evaluate the acute and sub-acute toxicity in male and female rats. The single dose (2000 mg/kg) of the extract was administered orally to male and female rats. In the subacute study the extract was given at doses of 100, 200 and 400mg/kg during 28 days orally. Biochemical, hematological and histological analyzes were performed, oxidative stress markers were tested and chemical constituents were identified through UHPLC-ESI-HRMS RESULTS: Six classes of metabolites were identified: iridoids glycosides, flavonoids, phenylpropanoids-derived, phenylethanoid-derived, cinnamic acid-derived and triterpenes. In the acute treatment, the extract was classified as safe (category 5), according to the OECD guide. Our results demonstrated that subacute administration of the crude extract of V. litoralis at 400mg/kg resulted in an increase in AST in males, whereas ALT enzyme showed a small increase in males that received 200mg/kg and 400mg/kg of the extract. The extract of the aerial parts of Verbena litoralis did not present significant toxicity when administered a single dose. However, when different doses were administered for 28 days, were observed changes in hematological, biochemical and histological parameters in rats. Copyright © 2018. Published by Elsevier B.V.

Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

PubMed

Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

2007-07-01

Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis

PubMed Central

Ladomenou, Fani; Carpenter, Ben; Chandra, Sharat; Sedlacek, Petr; Formankova, Renata; Grandage, Vicky; Friswell, Mark; Cant, Andrew J.; Nademi, Zohreh; Slatter, Mary A.; Gennery, Andrew R.; Hambleton, Sophie; Flood, Terence J.; Lucchini, Giovanna; Chiesa, Robert; Rao, Kanchan; Amrolia, Persis J.; Brogan, Paul; Wedderburn, Lucy R.; Glanville, Julie M.; Hough, Rachael; Marsh, Rebecca; Abinun, Mario; Veys, Paul

2018-01-01

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor–negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely. PMID:29618462

Ventilatory support in critically ill hematology patients with respiratory failure

PubMed Central

2012-01-01

Introduction Hematology patients admitted to the ICU frequently experience respiratory failure and require mechanical ventilation. Noninvasive mechanical ventilation (NIMV) may decrease the risk of intubation, but NIMV failure poses its own risks. Methods To establish the impact of ventilatory management and NIMV failure on outcome, data from a prospective, multicenter, observational study were analyzed. All hematology patients admitted to one of the 34 participating ICUs in a 17-month period were followed up. Data on demographics, diagnosis, severity, organ failure, and supportive therapies were recorded. A logistic regression analysis was done to evaluate the risk factors associated with death and NIVM failure. Results Of 450 patients, 300 required ventilatory support. A diagnosis of congestive heart failure and the initial use of NIMV significantly improved survival, whereas APACHE II score, allogeneic transplantation, and NIMV failure increased the risk of death. The risk factors associated with NIMV success were age, congestive heart failure, and bacteremia. Patients with NIMV failure experienced a more severe respiratory impairment than did those electively intubated. Conclusions NIMV improves the outcome of hematology patients with respiratory insufficiency, but NIMV failure may have the opposite effect. A careful selection of patients with rapidly reversible causes of respiratory failure may increase NIMV success. PMID:22827955

Targeting mTOR pathway in gynecological malignancies: Biological rationale and systematic review of published data.

PubMed

Kassem, Loay; Abdel-Rahman, Omar

2016-12-01

mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers. A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results. A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed. mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dandelion-enriched diet of mothers alleviates lead-induced damages in liver of newborn rats.

PubMed

Gargouri, M; Magné, C; Ben Amara, I; Ben Saad, H; El Feki, A

2017-02-28

Lead (Pb) is a highly toxic metal present in the environment. It causes disturbances of several functions, including hematologic, renal, reproductive and nervous ones. Preventive or curative use of medicinal plants against these disorders may be a promising and safe therapeutic strategy. This study evaluated the hepatic toxic effects of prenatal exposure to lead in rats and the possible protective effect of dandelion (Taraxacum officinale) added to the diet. Female rats were given a normal diet (control) or a diet enriched with dandelion (treated). In addition, lead acetate was administered to half of the rats through drinking water from the 5th day of gestation until the 14th day postpartum. Lead toxicity was evaluated in their offspring by measuring body and liver weights, plasma biochemical parameters, liver damage, as well as protein content and activities of antioxidant enzymes in the liver tissues. Lead poisoning of mothers caused lead deposition in blood and stomach of their pups as well as hepatic tissue damages. Moreover, significant decreases in liver weight and protein content were found. Lead treatment caused oxidative stress and marked changes in the activity of antioxidant enzymes. However, no damages or biochemical changes were observed in puppies from the rats co-treated with lead and dandelion. These results indicate that supplementation of pregnant and lactating rats with dandelion protects their offspring against lead poisoning, likely through reduction of oxidative stress and liver damages.

Subacute Oral Toxicity Study of Korean Red Ginseng Extract in Sprague-Dawley Rats

PubMed Central

Park, Sang-Jin; Lim, Kwang-Hyun; Noh, Jeong-Ho; Jeong, Eun Ju; Kim, Yong-Soon; Han, Byung-Cheol; Lee, Seung-Ho

2013-01-01

Ginseng is a well-known traditional medicine used in Asian countries for several thousand years, and it is currently applied to medicine, cosmetics, and nutritional supplements due to its many healing and energygiving properties. It is well demonstrated that ginsenosides, the main ingredient of ginseng, produce a variety of pharmacological and therapeutic effects on central nerve system (CNS) disorders, cardiovascular disease, endocrine secretions, aging, and immune function. Korean red ginseng extract is a dietary supplement containing ginsenoside Rb1 and ginsenoside Rg1 extracted from Panax ginseng. While the pharmacokinetics and bioavailability of the extract have been well established, its toxicological properties remain obscure. Thus, four-week oral toxicity studies in rats were conducted to investigate whether Korean red ginseng extract could have a potential toxicity to humans. The test article was administered once daily by oral gavage to four groups of male and female Sprague-Dawley (SD) rats at dose levels of 0, 500, 1,000, and 2,000 mg/kg/day for four weeks. Neither deaths nor clinical symptoms were observed in any group during the experiment. Furthermore, no abnormalities in body weight, food consumption, ophthalmology, urinalysis, hematology, serum biochemistry, gross findings, organ weights, or histopathology were revealed related to the administration of the test article in either sex of any dosed group. Therefore, a target organ was not determined in this study, and the no observed adverse effect level (NOAEL) of Korean red ginseng extract was established to be 2,000 mg/kg/day. PMID:24578799

[{sup 18}F]FDG-PET Standard Uptake Value as a Metabolic Predictor of Bone Marrow Response to Radiation: Impact on Acute and Late Hematological Toxicity in Cervical Cancer Patients Treated With Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elicin, Olgun; Callaway, Sharon; Prior, John O.

2014-12-01

Purpose: To quantify the relationship between bone marrow (BM) response to radiation and radiation dose by using {sup 18}F-labeled fluorodeoxyglucose positron emission tomography [{sup 18}F]FDG-PET standard uptake values (SUV) and to correlate these findings with hematological toxicity (HT) in cervical cancer (CC) patients treated with chemoradiation therapy (CRT). Methods and Materials: Seventeen women with a diagnosis of CC were treated with standard doses of CRT. All patients underwent pre- and post-therapy [{sup 18}F]FDG-PET/computed tomography (CT). Hemograms were obtained before and during treatment and 3 months after treatment and at last follow-up. Pelvic bone was autosegmented as total bone marrow (BM{sub TOT}).more » Active bone marrow (BM{sub ACT}) was contoured based on SUV greater than the mean SUV of BM{sub TOT}. The volumes (V) of each region receiving 10, 20, 30, and 40 Gy (V{sub 10}, V{sub 20}, V{sub 30}, and V{sub 40}, respectively) were calculated. Metabolic volume histograms and voxel SUV map response graphs were created. Relative changes in SUV before and after therapy were calculated by separating SUV voxels into radiation therapy dose ranges of 5 Gy. The relationships among SUV decrease, radiation dose, and HT were investigated using multiple regression models. Results: Mean relative pre-post-therapy SUV reductions in BM{sub TOT} and BM{sub ACT} were 27% and 38%, respectively. BM{sub ACT} volume was significantly reduced after treatment (from 651.5 to 231.6 cm{sup 3}, respectively; P<.0001). BM{sub ACT} V{sub 30} was significantly correlated with a reduction in BM{sub ACT} SUV (R{sup 2}, 0.14; P<.001). The reduction in BM{sub ACT} SUV significantly correlated with reduction in white blood cells (WBCs) at 3 months post-treatment (R{sup 2}, 0.27; P=.04) and at last follow-up (R{sup 2}, 0.25; P=.04). Different dosimetric parameters of BM{sub TOT} and BM{sub ACT} correlated with long-term hematological outcome. Conclusions: The volumes of BM{sub TOT} and BM{sub ACT} that are exposed to even relatively low doses of radiation are associated with a decrease in WBC counts following CRT. The loss in proliferative BM SUV uptake translates into low WBC nadirs after treatment. These results suggest the potential of intensity modulated radiation therapy to spare BM{sub TOT} to reduce long-term hematological toxicity.« less

Mucositis care in acute leukemia and non-Hodgkin lymphoma patients undergoing high-dose chemotherapy.

PubMed

Martinez, José Manuel; Pereira, Dulcineia; Chacim, Sérgio; Mesquita, Edgar; Sousa, Inês; Martins, Ângelo; Azevedo, Teresa; Mariz, José Mário

2014-09-01

This study intends to provide new insights into the incidence and care of mucositis by the epidemiological characterization of patients with hematological malignancy treated at our institution. It also aims to understand the effectiveness of several treatments used. This is a longitudinal observational single-center study-convenience sample-which includes malignant hematologic inpatients submitted to high-dose CT from February to August 2012. We registered epidemiological data, diagnosis, oral mucositis daily questionnaire (OMDQ), World Health Organization (WHO) oral toxicity scale, and supportive medications used for mucositis. We evaluated 30 patients who had 73 episodes of hospitalization, having recorded the development of mucositis in 21.9 % (n = 16) episodes (22 patients with acute leukemia (AL) and 8 patients with non-Hodgkin lymphoma (NHL)). Grades 3-4 mucositis was reported in 4.1 % of the total episodes. The results of OMDQ showed some limitations in the quality of life, of patients with mucositis, related with the ability to eat and drink due to mouth pain (p < 0.001). In patients with NHL and AL, neutropenia entails an increased risk of mucositis (p < 0.001). Patients who did not initiate early prophylaxis with conservative measures developed mucositis earlier (p < 0.05). The incidence of mucositis is high, being reported mainly in AL patients, with limitations in quality of life. Grade 4 neutropenia increases mucositis risk. Early prophylaxis with basic oral care may delay mucositis. Further studies are crucial to characterize mucositis epidemiology, physiopathology, and its management.

Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview.

PubMed

Singh, Anurag K; McGuirk, Joseph P

2016-11-15

The field of hematopoietic stem cell transplant (HSCT) has made ground-breaking progress in the treatment of many malignant and nonmalignant conditions. It has also pioneered the concepts of stem cell therapy and immunotherapy as a tool against cancer. The success of transplant for hematologic malignancies derives both from the ability to treat patients with intensive chemoradiotherapy and from potent graft-versus-leukemia (GVL) effects mediated by donor immunity. Additionally, HSCT has been a curative therapy for several nonmalignant hematologic disorders through the provision of donor-derived hematopoiesis and immunity. Preclinical and clinical research in the field has contributed to an advanced understanding of histocompatibility, graft-versus-host disease (GVHD), GVL effect, and immune reconstitution after transplant. Improved donor selection, tailored conditioning regimens, and better supportive care have helped reduce transplant-related morbidity and mortality and expanded access. The development of unrelated donor registries and increased utilization of cord blood and partially matched related donor transplants have ensured a donor for essentially everyone who needs a transplant. However, significant barriers still remain in the form of disease relapse, GVHD infectious complications, and regimen-related toxicities. Recent developments in the field of cellular therapy are expected to further improve the efficacy of transplant. In this review, we discuss the current science of HSCT from a historical perspective, highlighting major discoveries. We also speculate on future directions in this field. Cancer Res; 76(22); 6445-51. ©2016 AACR. ©2016 American Association for Cancer Research.

Dose-dependent increase in subjective symptoms among toluene-exposed workers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ukai, Hirohiko; Watanabe, Takao; Nakatsuka, Haruo

1993-02-01

A factory survey on dose-response relationship in toluene toxicity was conducted in 1985-1989 in four cities in China. The examination items consisted of personal diffusive sampling for TWA exposure measurement, questionnaires on subjective symptoms, hematology and serum biochemistry, and clinical examination including simple neurology tests. Hippuric acid was also determined in urine samples collected at the end of the shift. With selection criteria that (1) complete results were available on all study items and (2) valid toluene exposure data (i.e., toluene shared 90% or more of the exposure) were obtained for the exposed, 452 toluene-exposed workers (206 men and 246more » women; toluene exposure at 24.7 ppm as GM) and 517 nonexposed controls (246 men and 271 women) were selected. The subjective symptoms increased in close association with the intensity of exposure to toluene; the threshold concentration appeared to exist at 100 ppm in the case of symptoms during work, and it might be at 50-100 ppm when symptoms off work were evaluated. During the work with exposure at higher concentrations, various symptoms possibly related to CNS or local effects (e.g., eyes, nose, and throat) were complained, and dizziness and floating sensations were identified as typical symptoms with significant dose-response relationship. Several symptoms persisted off work, most of which were apparently related but not necessarily limited to CNS effects. Hematology and serum biochemistry were essentially negative. 46 refs., 4 figs., 6 tabs.« less

Bleeding frequency and characteristics among hematologic malignancy inpatient rehabilitation patients with severe thrombocytopenia.

PubMed

Fu, Jack B; Tennison, Jegy M; Rutzen-Lopez, Isabel M; Silver, Julie K; Morishita, Shinichiro; Dibaj, Seyedeh S; Bruera, Eduardo

2018-03-28

To identify the frequency and characteristics of bleeding complications during acute inpatient rehabilitation of hematologic malignancy patients with severe thrombocytopenia. Retrospective descriptive analysis. Comprehensive cancer center acute inpatient rehabilitation unit. Consecutive hematologic malignancy patients with a platelet count of less than or equal to 20,000/microliter (μL) on the day of acute inpatient rehabilitation admission from 1/1/2005 through 8/31/2016. Medical records were retrospectively analyzed for demographic, laboratory, and medical data. Patients were rehabilitated using the institutional exercise guidelines for thrombocytopenic patients. Bleeding events noted in the medical record. Out of 135 acute inpatient rehabilitation admissions, 133 unique patients were analyzed with a total of 851 inpatient rehabilitation days. The mean platelet count was 14,000/μL on the day of admission and 22,000/μL over the course of the rehabilitation admission. There were 252 days of inpatient rehabilitation where patients had less than 10,000/μL platelets. A total of 97 bleeding events were documented in 77/135 (57%) admissions. Of the 97 bleeding events, 72 (74%), 14 (14%), and 11 (11%) were considered to be of low, medium, and high severity, respectively. There were 4/97 (4%) bleeding events that were highly likely attributable to physical activity but only 1/4 was considered high severity. Bleeding rates were .09, .08, .17, and .37 for > 20,000, 15-20,000, 10-15,000, and < 10,000/μL mean platelet counts respectively (p = .003). Forty-four percent of patients were transferred back to the primary acute care service with infection being the most common reason for transfer. This study is the first to examine exercise-related bleeding complications during acute inpatient rehabilitation in severely thrombocytopenic hematologic cancer patients. Bleeding rates increased with lower platelet counts. However, using the exercise guidelines for severely thrombocytopenic patients, the risk of severe exercise-related bleeding events was low.

One-year dog toxicity study of D-002, a mixture of aliphatic alcohols.

PubMed

Alemán, C; Rodeiro, I; Noa, M; Menéndez, R; Gaméz, R; Hernandez, C; Más, R

2001-01-01

D-002 is a mixture of high-molecular-weight aliphatic alcohols, obtained from bees wax (Apis mellifera), with mild anti-inflammatory properties and effective anti-ulcer activities demonstrated in experimental models. This study investigated the oral toxicity of D-002 administered for 1 year to beagle dogs. Twenty-four beagle dogs (12 males and 12 females) were distributed randomly in three experimental groups (four animals per group): a control and two treated groups received D-002 at 50 and 250 mg kg(-1) (7 days/week) by gastric gavage. Overall, D-002 was well tolerated throughout the study. No signs or symptoms of toxicity were observed, and no mortality occurred during the study. All groups showed similar weight gain and food consumption. No hematological, blood biochemical or histopathological disturbances attributable to treatment were observed. This study shows no drug-related toxicity induced by long-term administration of up to 250 mg kg(-1) D-002 to beagle dogs. Copyright 2001 John Wiley & Sons, Ltd.

FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

PubMed Central

Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar; Champlin, Richard E.; Ciurea, Stefan O.

2015-01-01

Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem-cell transplantation. From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantation due to its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas; and has been used successfully in preparative regimens of a variety of other hematological and non-hematological malignancies. The addition of newer agents to conditioning like bortezomib or lenalidomide for myeloma, or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, while in combination with alemtuzumab may represent a backbone for future cellular therapy due to reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic stem-cell transplantation. PMID:22922522

Toxicological parameters of albino rats fed with extruded snacks from Aerial yam (Dioscoria bulbifera) and African breadfruit seed (Treculia africana).

PubMed

Olatoye, Kazeem K; Arueya, Gibson L

2018-01-01

In this study, safety of novel food from aerial yam and Treculia africana , underutilized food materials with high-nutritive value and health benefits were investigated. Animal experiment involving the use of thirty (30) male albino rats was conducted for 28 days.Thereafter, rats in all groups were sacrificed and blood samples collected for biochemical analysis and hematological assay. Some vital organs were harvested and used for histological analysis. Biochemical and hematological parameters were not significantly p  ≤ .05 different among the treatment and controls. However there was an increase in monocytes, which is a reflection of immune boosting potential of the novel snack. No significant pathological changes were observed in liver and kidney of rats fed with this snack. Rats showed no signs of toxicity within the study period. These findings suggest that product may be safe and useful as an Immune adjuvant.

First report of changes in leukocyte morphology in response to inflammatory conditions in Asian and African elephants (Elephas maximus and Loxodonta africana).

PubMed

Stacy, Nicole I; Isaza, Ramiro; Wiedner, Ellen

2017-01-01

Although the hematology of healthy elephants has been well-described, published information on hematological changes during disease is limited. The objective of this study was to describe qualitative morphological changes in the leukocytes of Asian and African elephants (Elephas maximus and Loxodonta africana) diagnosed with a variety of inflammatory conditions. Twenty-five of 27 elephants had morphological changes in their leukocytes, although only 16 of these had a concurrent inflammatory leukogram. Morphological changes included heterophil left-shifting with or without concurrent dysgranulopoiesis, toxicity, or hypersegmentation, reactive lymphocytes, plasma cells, and/or vacuolated monocytes. Although the observed leukocyte morphological changes are non-specific, their early recognition upon blood film evaluation may provide important, clinically-relevant information, particularly if the leukogram is normal. This case series is the first description of qualitative morphological changes in the leukocytes of elephants in association with inflammation.

First report of changes in leukocyte morphology in response to inflammatory conditions in Asian and African elephants (Elephas maximus and Loxodonta africana)

PubMed Central

Isaza, Ramiro; Wiedner, Ellen

2017-01-01

Although the hematology of healthy elephants has been well-described, published information on hematological changes during disease is limited. The objective of this study was to describe qualitative morphological changes in the leukocytes of Asian and African elephants (Elephas maximus and Loxodonta africana) diagnosed with a variety of inflammatory conditions. Twenty-five of 27 elephants had morphological changes in their leukocytes, although only 16 of these had a concurrent inflammatory leukogram. Morphological changes included heterophil left-shifting with or without concurrent dysgranulopoiesis, toxicity, or hypersegmentation, reactive lymphocytes, plasma cells, and/or vacuolated monocytes. Although the observed leukocyte morphological changes are non-specific, their early recognition upon blood film evaluation may provide important, clinically-relevant information, particularly if the leukogram is normal. This case series is the first description of qualitative morphological changes in the leukocytes of elephants in association with inflammation. PMID:28934325

Chimeric Antigen Receptor T Cells and Hematopoietic Cell Transplantation: How Not to Put the CART Before the Horse

PubMed Central

Kenderian, Saad S.; Porter, David L.; Gill, Saar

2016-01-01

Hematopoietic cell transplantation (HCT) remains an important and potentially curative option in most hematological malignancies. As a form of immunotherapy, allogeneic HCT offers the potential for durable remissions but is limited by transplant related morbidity and mortality due to organ toxicity, infection and graft versus host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematological malignancies. Clinical trials will now need to address the relative roles of CART cells and HCT in the context of transplant-eligible patients. In this review we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT. PMID:27638367

Improved survival for elderly married glioblastoma patients : Better treatment delivery, less toxicity, and fewer disease complications.

PubMed

Putz, Florian; Putz, Tobias; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Eyüpoglu, Ilker; Rössler, Karl; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer

2016-11-01

Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers

PubMed Central

Tekwani, Babu L.; Herath, H. M. T. Bandara; Sahu, Rajnish; Gettayacamin, Montip; Tungtaeng, Anchalee; van Gessel, Yvonne; Baresel, Paul; Wickham, Kristina S.; Bartlett, Marilyn S.; Fronczek, Frank R.; Melendez, Victor; Ohrt, Colin; Reichard, Gregory A.; McChesney, James D.; Rochford, Rosemary; Walker, Larry A.

2014-01-01

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (−)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (−)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(R)-PQ may have a better safety margin than the racemate in human. PMID:24913163

Weekly Low-Dose Docetaxel-Based Chemoradiotherapy for Locally Advanced Oropharyngeal or Hypopharyngeal Carcinoma: A Retrospective, Single-Institution Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukada, Junichi, E-mail: fukada@sc.itc.keio.ac.j; Shigematsu, Naoyuki; Takeda, Atsuya

2010-02-01

Purpose: To retrospectively assess the efficacy, toxicity, and prognostic factors of weekly low-dose docetaxel-based chemoradiotherapy for Stage III/IV oropharyngeal or hypopharyngeal carcinoma. Methods and Materials: Between 2001 and 2005, 72 consecutive patients with locally advanced oropharyngeal or hypopharyngeal carcinoma were treated with concurrent chemoradiotherapy (CCR; radiation at 60 Gy plus weekly docetaxel [10 mg/m{sup 2}]). Thirty of these patients also received neoadjuvant chemotherapy (NAC; docetaxel, cisplatin, and 5-fluorouracil) before concurrent chemoradiotherapy. Survival was calculated according to the Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses. Results: The median follow-up was 33 months, with overall survival, disease-freemore » survival, and locoregional control rates at 3 years of 59%, 45%, and 52%, respectively. Thirty-six patients (50%) experienced more than one Grade 3 to 4 acute toxicity. Grade 3 mucositis occurred in 32 patients (44%), Grade 4 laryngeal edema in 1 (1%). Grade >=3 severe hematologic toxicity was observed in only 2 patients (3%). Grade 3 dysphagia occurred as a late complication in 2 patients (3%). Multivariate analyses identified age, T stage, hemoglobin level, and completion of weekly docetaxel, but not NAC, as significant factors determining disease-free survival. Conclusions: Docetaxel is an active agent used in both concurrent and sequential chemoradiotherapy regimens. Mucositis was the major acute toxicity, but this was well tolerated in most subjects. Anemia was the most significant prognostic factor determining survival. Further studies are warranted to investigate the optimal protocol for integrating docetaxel into first-line chemoradiotherapy regimens, as well as the potential additive impact of NAC.« less

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

PubMed

Hohloch, Karin; Zeynalova, Samira; Chapuy, Björn; Pfreundschuh, Michael; Loeffler, Markus; Ziepert, Marita; Feller, Alfred C; Trümper, Lorenz; Hasenclever, Dirk; Wulf, Gerald; Schmitz, Norbert

2016-06-01

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Autologous bone marrow purging with LAK cells.

PubMed

Giuliodori, L; Moretti, L; Stramigioli, S; Luchetti, F; Annibali, G M; Baldi, A

1993-12-01

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data made LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

Meeting the challenge of hematologic malignancies in sub-Saharan Africa

PubMed Central

Wood, William A.; Lee, Stephanie J.; Shea, Thomas C.; Naresh, Kikkeri N.; Kazembe, Peter N.; Casper, Corey; Hesseling, Peter B.; Mitsuyasu, Ronald T.

2012-01-01

Cancer is a leading cause of death and disability in sub-Saharan Africa and will eclipse infectious diseases within the next several decades if current trends continue. Hematologic malignancies, including non-Hodgkin lymphoma, leukemia, Hodgkin lymphoma, and multiple myeloma, account for nearly 10% of the overall cancer burden in the region, and the incidence of non-Hodgkin lymphoma and Hodgkin lymphoma is rapidly increasing as a result of HIV. Despite an increasing burden, mechanisms for diagnosing, treating, and palliating malignant hematologic disorders are inadequate. In this review, we describe the scope of the problem, including the impact of endemic infections, such as HIV, Epstein-Barr virus, malaria, and Kaposi sarcoma–associated herpesvirus. We additionally describe current limitations in hematopathology, chemotherapy, radiotherapy, hematopoietic stem cell transplantation, and supportive care and palliation. We review contemporary treatment and outcomes of hematologic malignancies in the region and outline a clinical service and research agenda, which builds on recent global health successes combating HIV and other infectious diseases. Achieving similar progress against hematologic cancers in sub-Saharan Africa will require the sustained collaboration and advocacy of the entire global cancer community. PMID:22461494

Subchronic toxicity study in vivo and allergenicity study in vitro for genetically modified rice that expresses pharmaceutical protein (human serum albumin).

PubMed

Sheng, Yao; Qi, Xiaozhe; Liu, Yifei; Guo, Mingzhang; Chen, Siyuan; He, Xiaoyun; Huang, Kunlun; Xu, Wentao

2014-10-01

Genetically modified (GM) crops that express pharmaceutical proteins have become an important focus of recent genetic engineering research. Food safety assessment is necessary for the commercial development of these crops. Subchronic toxicity study in vivo and allergenicity study in vitro were designed to evaluate the food safety of the rice variety expressing human serum albumin (HSA). Animals were fed rodent diets containing 12.5%, 25.0% and 50.0% GM or non-GM rice for 90 days. The composition analysis of the GM rice demonstrated several significant differences. However, most of the differences remained within the ranges reported in the literature. In the animal study, a range of indexes including clinical observation, feed efficiency, hematology, serum chemistry, organ weights and histopathology were examined. Random changes unrelated to the GM rice exposure, within the range of historical control values and not associated with any signs of illness were observed. The results of heat stability and in vitro digestion of HSA indicated no evidence of potential allergenicity of the protein. Overall, the results of these studies suggest that the GM rice appears to be safe as a dietary ingredient when it is used at up to 50% in the diet on a subchronic basis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hematology and serum biochemistry comparison in wild and captive Central American river turtles (Dermatemys mawii) in Tabasco, Mexico.

PubMed

Rangel-Mendoza, Judith; Weber, Manuel; Zenteno-Ruiz, Claudia E; López-Luna, Marco A; Barba-Macías, Everardo

2009-10-01

Hematological and serum biochemistry analyses were determined on 51 Central American river turtles (Dermatemys mawii) during the dry and rainy seasons of 2006. Turtles came from two sites: Pantanos de Centla Biosphere Reserve and a turtle breeding farm, both located in Tabasco State, Mexico. Physical examination and body measures of animals were performed. Incidence and prevalence of hemoparasites were explored. Captive organisms were in poor physical condition while wild turtles were apparently healthy. There were differences in several hematological parameters related with the condition and the season. During the dry season captive turtles exhibited higher levels of uric acid and urea, as well as lower levels of glucose. Haemogregarina sp. was detected in 100% of the wild individuals, but not in captive individuals. Its incidence was greater during the rainy season. This is the first health assessment and hematology study of this critically endangered species.

A subchronic oral toxicity study of Salacia reticulata extract powder in rats.

PubMed

Oda, Yuriko; Yuasa, Atsuko; Ueda, Fumitaka; Kakinuma, Chihaya

2015-01-01

The safety of Salacia plant ( Salacia reticulata ) extract powder, which is used in Ayurvedic medical practices, was studied in a dose range-finding subchronic toxicity study in Crl:CD Sprague-Dawley rats. Male and female rats were randomly assigned to 4 treatment groups and were treated by oral gavage with 0, 10, 65, and 400 mg/kg body weight/day of the powder for 91 days. Body weight, food consumption, and clinical signs were assessed during the treatment period. Urinalysis, hematology, blood chemistry, and organ weights were determined one day after the final treatment. The animals were euthanized at the end of the treatment and were examined for necropsy and histopathological purposes. No adverse toxicity was observed in the Salacia powder-treated groups with a No Observed Adverse Effect Level of ≧400 mg/kg body weight/day in both male and female SD rats.

Investigation of chronic toxicity of hydroxyapatite nanoparticles administered orally for one year in wistar rats.

PubMed

Remya, N S; Syama, S; Sabareeswaran, A; Mohanan, P V

2017-07-01

Although the toxicity/biocompatibility of hydroxyapatite nanoparticles (nano HA), a prospective nano biomaterial is extensively studied, its interaction on biological systems following chronic exposure is less exploited. In the present study, Wistar rats were given various concentrations of nano HA in the diet to determine the chronic toxicity and potential carcinogenicity. Altogether 140 rats were used for the study under various administration dosages along with control. The animals were sacrificed after 12months of controlled continuous dosing. All in-life parameters, including body weight, food consumption, clinical observations, survival, biochemical and hematology, were unaffected by the chronic exposure of nano HA orally. Similarly, gross and histopathological evaluation was also unchanged following exposure to nano HA. No evidence of nano HA-related lesions or Nano HA-induced neoplasia was suggested in this rodent bioassay study. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxicity study of isolated polypeptide from wool hydrolysate.

PubMed

Li, Jiashen; Li, Yi; Zhang, Yu; Liu, Xuan; Zhao, Zheng; Zhang, Jing; Han, Yanxia; Zhou, Dangxia

2013-07-01

The cytotoxicity of wool polypeptide has been evaluated by both cell and animal models. Wool was dissolved in sodium hydroxide solution, the pH value of the solution was adjusted to 5.55 and the precipitate was harvested as wool polypeptide. The spray-dried polypeptide was collected as powders and characterized by SEM, FTIR and TG-DSC. The cell culturing results showed that wool polypeptide had no obvious negative effect on cell viability in vitro. Both acute oral toxicity and subacute 30-day oral toxicology studies showed that wool polypeptide had no influence on body weight, feed consumption, blood chemistry, and hematology at any dose levels. There were no treatment related findings on gross or detailed necroscopy, organ weights, organ/body weight ratios and histology. Our study indicated the absence of toxicity in wool polypeptide and supported its safe use as a food ingredient or drug carrier. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antimicrobial, antioxidant, toxicity and phytochemical assessment of extracts from Acmella uliginosa, a leafy-vegetable consumed in Bénin, West Africa.

PubMed

Lagnika, Latifou; Amoussa, Abdou Madjid O; Adjileye, Rafatou A A; Laleye, Anatole; Sanni, Ambaliou

2016-01-27

Acmella uliginosa (Asteraceae) is a flowering plant whose leaves are consumed as a vegetable in Benin. They are also traditionally used as an antibiotic in the treatment of infectious diseases. To evaluate the therapeutic potential and toxicity effect of this leafy-vegetable, the antibacterial, antifungal, antioxidant activities and, toxicity and phytochemical constituents were investigated. Dichloromethane, methanol and aqueous extracts of Acmella uliginosa were evaluated for their antimicrobial activity against six bacterial and six fungi strains. Antibacterial and antifungal activities were investigated by microdilution method and agar diffusion method respectively. Antioxidant activity was assessed using the 2,2-diphenyl-1-picryl-hydrazyl assay and phytochemical screening was carried out using standard procedures. Finally, oral acute toxicity at a dose of 2000 mg/kg was done according to the Organization for Economic Co-operation and Development guideline n° 423. The antibacterial activity was broad spectrum, inhibiting both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration ranged from 0.625 to 5 mg/ml. The antifungal evaluation show that all the extracts inhibited mycelial growth and sporulation of fungi with percentages of inhibition ranging from 9.39 to 75.67% and 22.04 to 99.77%, respectively. In DPPH radical scavenging assay, the effect on reducing free radicals increased in a dose dependent manner. The percentage of inhibition of DPPH ranged from 0.94 to 73.07%. Phytochemical screening revealed the presence of coumarin, flavonoid, naphtoquinone, anthracene derivative, saponin, lignan, triterpene and tannin. The dichloromethane and methanol extracts showed the best biological activities; they were also shown as the best extraction solvents of phytochemicals. In the acute toxicity evaluation, all animals were physically active and no deaths of rats were observed during the test. However, the aqueous extract promoted biochemical, hematological and histopathological alterations of treated rats at 2000 mg/kg body weight. A. uliginosa extracts contains antimicrobial, antioxidant agents and was not lethal for rats when ingested. However, according to the results obtained for biochemical, hematological, and histopathological analysis, caution is required regarding its consumption.

Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.

PubMed

Dickson, Mark A; Schwartz, Gary K; Keohan, Mary Louise; D'Angelo, Sandra P; Gounder, Mrinal M; Chi, Ping; Antonescu, Cristina R; Landa, Jonathan; Qin, Li-Xuan; Crago, Aimee M; Singer, Samuel; Koff, Andrew; Tap, William D

2016-07-01

More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects. To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. Primary end point was PFS. Secondary end points included response rate and toxic effects. Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. clinicaltrials.gov Identifier: NCT01209598.

Helical Tomotherapy With Simultaneous Integrated Boost After Laparoscopic Staging in Patients With Cervical Cancer: Analysis of Feasibility and Early Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marnitz, Simone, E-mail: simone.marnitz@charite.de; Koehler, Christhardt; Burova, Elena

Purpose: To demonstrate the feasibility and safety of the simultaneous integrated boost technique for dose escalation in combination with helical tomotherapy in patients with cervical cancer. Methods and Materials: Forty patients (International Federation of Gynecology and Obstetrics Stage IB1 pN1-IVA) underwent primary chemoradiation with helical tomotherapy. Before therapy, 29/40 patients underwent laparoscopic pelvic and para-aortic lymphadenectomy. In 21%, 31%, and 3% of the patients, pelvic, pelvic and para-aortic, and skip metastases in the para-aortic region could be confirmed. All patients underwent radiation with 1.8-50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (planning target volume-A), andmore » a simultaneous boost with 2.12-59.36 Gy to the boost region (planning target volume-B). The boost region was defined using titan clips during laparoscopic staging. In all other patients, standardized borders for the planning target volume-B were defined. High-dose-rate brachytherapy was performed in 39/40 patients. The mean biologic effective dose to the macroscopic tumor ranged from 87.5 to 97.5 Gy. Chemotherapy consisted of weekly cisplatin 40 mg/m{sup 2}. Dose-volume histograms and acute gastrointestinal, genitourinary, and hematologic toxicity were evaluated. Results: The mean treatment time was 45 days. The mean doses to the small bowel, rectum, and bladder were 28.5 {+-} 6.1 Gy, 47.9 {+-} 3.8 Gy, and 48 {+-} 3 Gy, respectively. Hematologic toxicity Grade 3 occurred in 20% of patients, diarrhea Grade 2 in 5%, and diarrhea Grade 3 in 2.5%. There was no Grade 3 genitourinary toxicity. All patients underwent curettage 3 months after chemoradiation, which confirmed complete pathologic response in 38/40 patients. Conclusions: The concept of simultaneous integrated boost for dose escalation in patients with cervical cancer is feasible, with a low rate of acute gastrointestinal and genitourinary toxicity. Whether dose escalation can be translated into improved outcome will be assessed after a longer follow-up time.« less

Cassia grandis fruit extract reduces the blood glucose level in alloxan-induced diabetic rats.

PubMed

Prada, Ariadna Lafourcade; Amado, Jesús Rafael Rodríguez; Keita, Hady; Zapata, Edgar Puente; Carvalho, Helison; Lima, Emersom Silva; de Sousa, Tatiane Pereira; Carvalho, José Carlos Tavares

2018-04-16

Cassia grandis Lf fruits are ethnobotanically used for digestive disorders, anemia, and for reducing blood glucose. However, there are no studies about the antidiabetic activity nor the oral toxicity of the plant fruit-extracts. This paper aims to evaluate the hypoglycemic effect of C. grandis fruits extract in vivo, and assess the acute oral toxicity, and sub-acute oral toxicity. The antioxidant activity and the α-glycosidase inhibitor effect were also evaluated. The extract was obtained by maceration of the fruit pulp with 70% hydroalcoholic solution (1:2, m:v). The extractive solution was concentrated in a vacuum rotary evaporator, up to a drug: solvent ratio of 2:1 (g/ml). Soluble solids, relative density, refractive index, pH, total phenolics, and flavonoids were determined. A preliminary phytochemical screening was made, followed by the quantitation of volatiles by GC/MS. The acute and sub-acute oral toxicity was evaluated in Sprague Dawley rats, by using biochemical and hematological parameters. The radical scavenging activity (DPPH, ABTS) and α-glycosidase inhibitory effect were tested. The hypoglycemic effect was assessed in alloxan-induced diabetic rats. The extract of C. grandis contains alkaloids, coumarins, flavonoids, free amino acids, amines, phenols, tannins, reduced sugars, resins, saponins, steroids, and triterpenes, plus 38 volatile compounds, being linalool the most abundant (1,66%). The extract exhibited an LD 50  > 2000 mg/kg, and after a continuous administration (1000 mg/kg, 28-days), the hematological and biochemical parameters were normal. The extract showed hypoglycemic effect, being the dose 200 mg/kg no statistically different from glibenclamide at 25 mg/kg. Good antioxidant activity and a potent α-glycosidase inhibitory effect were also observed. C. grandis extract is an excellent hypoglycemic and non-toxic plant product. The hypoglycemic mechanism could be associated with the antioxidant effect and with the α-glycosidase inhibition. Up to the best of our knowledge, this is the first report on the hypoglycemic effect in vivo of C. grandis fruits extract. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?

PubMed

Hamaker, M E; Stauder, R; van Munster, B C

2014-03-01

Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population.

HIV-associated hematologic malignancies: Experience from a Tertiary Cancer Center in India.

PubMed

Reddy, Rakesh; Gogia, Ajay; Kumar, Lalit; Sharma, Atul; Bakhshi, Sameer; Sharma, Mehar C; Mallick, Saumyaranjan; Sahoo, Ranjit

2016-01-01

Data on HIV associated hematologic malignancies is sparse from India. This study attempts to analyze the spectrum and features of this disease at a tertiary cancer center in India. Retrospective study from case records of patients registered with a diagnosis of hematologic malignancy and HIV infection between January 2010 and June 2015. Thirteen cases of HIV associated hematologic malignancies were identified, six of them pediatric. HIV diagnosis was concurrent to diagnosis of cancer in 12 and preceded it in one of them. ECOG PS at presentation was >1 in all of them. All patients, except one, had B symptoms. Six of the patients had bulky disease and six are stage 4. Predominant extranodal disease was seen in 67% of them. NHL accounted for 10 of 13 patients and DLBCL-Germinal center was the most common subtype. Mean CD4+ cell count was 235/μL (range, 32-494). HAART could be given along with chemotherapy to 11 patients. Two-thirds of patients received standard doses of therapy. Chemo-toxicity required hospitalization in 58%. CR was achieved in 45% and 36% had progressive disease with first-line therapy. At the time of last follow up, 3 patients were alive with responsive disease, 2 in CR and 1 in PR. None of the pediatric patients were long time responders. These malignancies were of advanced stage and higher grade. Goal of therapy, in the HAART era, is curative. Pediatric patients had dismal outcome despite good chemotherapy and HAART. There is an urgent need to improve data collection for HIV related cancers in India.

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?†

PubMed Central

Hamaker, M. E.; Stauder, R.; van Munster, B. C.

2014-01-01

Background Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. Method The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. Results In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Conclusion Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population. PMID:24458474

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells.

PubMed

Allegra, Alessandro; Innao, Vanessa; Gerace, Demetrio; Vaddinelli, Doriana; Musolino, Caterina

2016-11-01

Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors. CAR-T treatment has emerged as a promising approach for patients with hematological malignancies, and there are several works reporting clinical trials of the use of CAR-modified T-cells in acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, lymphoma, and in acute myeloid leukemia by targeting different antigens. This review reports the history of adoptive immunotherapy using CAR-Ts, the CAR-T manufacturing process, and T cell therapies in development for hematological malignancies. Copyright © 2016 Elsevier Inc. All rights reserved.

Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology.

PubMed

Akin, C; Schwartz, L B; Kitoh, T; Obayashi, H; Worobec, A S; Scott, L M; Metcalfe, D D

2000-08-15

Systemic mastocytosis is a disease of mast cell proliferation that may be associated with hematologic disorders. There are no features on examination that allow the diagnosis of systemic disease, and mast cell-derived mediators, which may be elevated in urine or blood, may also be elevated in individuals with severe allergic disorders. Thus, the diagnosis usually depends on results of bone marrow biopsy. To facilitate evaluation, surrogate markers of the extent and severity of the disease are needed. Because of the association of mastocytosis with hematologic disease, plasma levels were measured for soluble KIT (sKIT) and soluble interleukin-2 receptor alpha chain (sCD25), which are known to be cleaved in part from the mast cell surface and are elevated in some hematologic malignancies. Results revealed that levels of both soluble receptors are increased in systemic mastocytosis. Median plasma sKIT concentrations as expressed by AU/mL (1 AU = 1.4 ng/mL) were as follows: controls, 176 (n = 60); urticaria pigmentosa without systemic involvement, 194 (n = 8); systemic indolent mastocytosis, 511 (n = 30); systemic mastocytosis with an associated hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3). Plasma sCD25 levels were elevated in systemic mastocytosis; the highest levels were associated with extensive bone marrow involvement. Levels of sKIT correlated with total tryptase levels, sCD25 levels, and bone marrow pathology. These results demonstrate that sKIT and sCD25 are useful surrogate markers of disease severity in patients with mastocytosis and should aid in diagnosis, in the selection of those needing a bone marrow biopsy, and in the documentation of disease progression. (Blood. 2000;96:1267-1273)

Toxicological evaluations of Stigma maydis (corn silk) aqueous extract on hematological and lipid parameters in Wistar rats.

PubMed

Saheed, Sabiu; Oladipipo, Ajani E; Abdulazeez, Abubakar A; Olarewaju, Sulyman A; Ismaila, Nurain O; Emmanuel, Irondi A; Fatimah, Quadri D; Aisha, Abubakar Y

2015-01-01

Despite the acclaimed phytotherapeutic attributes of Stigma maydis in folkloric medicine, there is paucity of information on its toxicity profile on hematological and lipid parameters. The toxicological effect of aqueous extract of corn silk at 100, 200 and 400 mg/kg body weight on hematological indices in Wistar rats were evaluated progressively at 24 h after 1, 7, 14, 21 and 28 days. Lipid parameters were also analyzed at the end of the experimental period. We observed that the extract did not exhibit any significant ( p  > 0.05) effect on red blood cells, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and mean platelet volume at all the tested doses. The study however showed a significant increase in the serum levels of white blood cell, platelet, lymphocytes, high-density lipoprotein cholesterol; as well as feeding pattern in the animals, while the concentrations of total cholesterol, low-density lipoprotein cholesterol, and artherogenic index value were significantly lowered. These findings are suggestive of non-hematotoxic potential of the extract. Overall, the effect exhibited by corn silk extract in this study proved that, it is unlikely to be hematotoxic and could be a good candidature in the management of coronary heart diseases if consumed at the doses investigated.

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

PubMed Central

2013-01-01

Background Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. Methods Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. Results At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. Conclusions VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity. PMID:24168457

Hematological disorders at birth in complicated monochorionic twins.

PubMed

Verbeek, Lianne; Slaghekke, Femke; Sueters, Marieke; Middeldorp, Johanna M; Klumper, Frans J; Haak, Monique C; Oepkes, Dick; Lopriore, Enrico

2017-06-01

Monochorionic twins are at risk of severe complications including twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS) and acute peripartum TTTS. The pathophysiology is based on inter-twin blood transfusion through placental vascular anastomoses. Areas covered: This review focuses on the incidence, management and outcome of neonatal hematological complications at birth in TTTS, TAPS and acute peripartum TTTS. Expert commentary: Hematological disorders are often present at birth in monochorionic twins and include acute or chronic anemia, polycythemia and thrombocytopenia. Routine measurement of complete blood counts in all complicated monochorionic twins is strongly recommended. Increased awareness on these disorders and correct diagnostic tests will lead to prompt and adequate management at birth.

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

PubMed

Samkoe, Kimberley S; Gunn, Jason R; Marra, Kayla; Hull, Sally M; Moodie, Karen L; Feldwisch, Joachim; Strong, Theresa V; Draney, Daniel R; Hoopes, P Jack; Roberts, David W; Paulsen, Keith; Pogue, Brian W

2017-08-01

ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use. Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490 μg/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14 days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively. Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye. Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5 mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

PubMed

Walter, Harriet S; Rule, Simon A; Dyer, Martin J S; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, Gilles

2016-01-28

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. © 2016 by The American Society of Hematology.

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.

PubMed

Yamashita, Fumiaki; Komoto, Ikumi; Oka, Hiroaki; Kuwata, Keizo; Takeuchi, Mayuko; Nakagawa, Fumio; Yoshisue, Kunihiro; Chiba, Masato

2015-08-01

Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review.

PubMed

Miyamoto, Morikazu; Takano, Masashi; Kuwahara, Mika; Soyama, Hiroaki; Kato, Kento; Matuura, Hiroko; Sakamoto, Takahiro; Takasaki, Kazuki; Aoyama, Tadashi; Yoshikawa, Tomoyuki; Furuya, Kenichi

2018-01-01

We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70 mg/m 2 of CPT-11 on days 1, 8, and 15, and 50 mg/m 2 of nedaplatin on day 1, q4 weeks. The median patient age was 63 years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

A comprehensive toxicity study of zinc oxide nanoparticles versus their bulk in Wistar rats: Toxicity study of zinc oxide nanoparticles.

PubMed

Srivastav, Anurag Kumar; Kumar, Mahadeo; Ansari, Nasreen Ghazi; Jain, Abhishek Kumar; Shankar, Jai; Arjaria, Nidhi; Jagdale, Pankaj; Singh, Dhirendra

2016-12-01

The purpose of this study was to characterize the zinc oxide nanoparticles (ZnO-NPs) and their bulk counterpart in suspensions and to access the impact of their acute oral toxicity at doses of 300 and 2000 mg/kg in healthy female Wistar rats. The hematological, biochemical, and urine parameters were accessed at 24 and 48 h and 14 days posttreatment. The histopathological evaluations of tissues were also performed. The distribution of zinc content in liver, kidney, spleen, plasma, and excretory materials (feces and urine) at 24 and 48 h and 14 days posttreatment were accessed after a single exposure at dose of 2000 mg/kg body weight. The elevated level of alanine amino transferase, alkaline phosphatase, lactate dehydrogenase, and creatinine were observed in ZnO-NPs at a dose of 2000 mg/kg at all time points. There was a decrease in iron levels in all the treated groups at 24 h posttreatment as compared to control groups but returned to their normal level at 14 days posttreatment. The hematological parameters red blood cells, hemoglobin, hematocrit, platelets, and haptoglobin were reduced at 48 h posttreatment at a dose of 2000 mg/kg ZnO-NPs and showed hemolytic condition. All the treated groups were comparable to control group at the end of 14 days posttreatment. The zinc concentration in the kidney, liver, plasma, feces, and urine showed a significant increase in both groups as compared to control. This study explained that ZnO-NPs produced more toxicological effect as compared to their bulk particles as evidenced through alteration in some hemato-biochemical parameters and with few histopathological lesions in liver and kidney tissues. © The Author(s) 2016.

Hematologic and Biochemical Values of Wild Red-Tailed Amazon Parrot (Amazona brasiliensis) Nestlings With Abnormal Clinical Examination in Rasa Island, Brazil.

PubMed

Vaz, Frederico Fontanelli; Locatelli-Dittrich, Rosangela; Beltrame, Olair Carlos; Sipinski, Elenise Angelotti Bastos; Abbud, Maria Cecília; Sezerban, Rafael Meirelles

2016-12-01

The red-tailed Amazon parrot (Amazona brasiliensis) is an endangered psittacine species, but little information is available about abnormal clinical findings and hematologic and biochemical values of this species, which are important for monitoring the health of this population. To determine hematologic and biochemical values for wild red-tailed parrot nestlings exhibiting abnormal clinical findings, 31 nestlings from the Rasa Island (Paraná State, Southern Brazil) were physically restrained for clinical examination and blood sample collection. On physical examination, 26 birds had mild abnormalities and 5 had severe disorders. Parrots were divided into 5 groups according to the following clinical findings: presence of ectoparasites (group 1), respiratory disorders (group 2), chronic skin lesions caused by fly larvae (group 3), beak disorders (group 4), and severe clinical signs (group 5). Abnormal hematologic and biochemical findings in the nestlings were high total protein in group 3; low values for hemoglobin and mean corpuscular hemoglobin concentration in group 4; low glucose concentration, high mean absolute heterophil count, and high heterophil : lymphocyte ratio in group 5; high concentrations of total plasma protein in groups 3 and 4; and high globulin concentration in groups 3 and 5. In general, the population assessed was in good condition. These results provide a guide to the expected clinical findings associated with hematologic and biochemical concentrations in a population of free-living parrots with abnormal clinical examination findings. The data support the conservation planning and health monitoring of the endangered red-tailed Amazon parrot.

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com; Flagella, Kelly; Beyer, Joseph

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeysmore » and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and pharmacologic activity. • When conjugated in T-DM1, higher doses of DM1 can be tolerated. • Antibody-drug conjugates may improve the therapeutic window for cytotoxic agents.« less

Genotoxicity, acute and subchronic toxicity studies in rats of a rooster comb extract rich in sodium hyaluronate.

PubMed

Canut, Lourdes; Zapatero, Jorge; López, Sílvia; Torrent, Anna; Ruhí, Ramon; Vicente, Laura

2012-04-01

The toxicity of a rooster comb extract (IB0004) that contains mainly sodium hyaluronate was assessed in acute and subchronic studies and in a bacterial reverse mutation assay. In a single dose acute study, male and female rats were administered 2000 mg/kg body weight (bw) of the product and observed for 14 days. No mortality was recorded, thus it was considered that the minimum lethal dose for rats by oral route was greater than 2000 mg/kg bw. A 90-day subchronic study (5, 55 and 600 mg/kg bw/day, oral gavage) with 50 male and 50 female Wistar-Hannover rats produced no significant adverse effects on food consumption, body weight, mortality, clinical biochemistry, hematology, gross pathology, and histopathology. Although some differences were observed between the treated and control animals in body weight gain (%) and some hematological parameters, these changes were generally minor in nature and, are considered to be of no toxicological significance. The no-observable-adverse-effects level was established at 600 mg/kg bw/day. There was no evidence of mutagenic activity in Salmonella typhimurium TA98, TA100, TA1535 and TA1537 or in Escherichia coli WP2 uvra pkM101. In conclusion, the results from these safety studies support the safety of rooster comb extract IB0004 in food. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of Cytotoxicity, Genotoxicity and Hematotoxicity of the Recombinant Spore-Crystal Complexes Cry1Ia, Cry10Aa and Cry1Ba6 from Bacillus thuringiensis in Swiss Mice

PubMed Central

de Souza Freire, Ingrid; Miranda-Vilela, Ana Luisa; Barbosa, Lilian Carla Pereira; Martins, Erica Soares; Monnerat, Rose Gomes; Grisolia, Cesar Koppe

2014-01-01

The insecticidal properties of Cry-endotoxins from Bacillus thuringiensis (Bt) have long been used as spore-crystals in commercial spray formulations for insect control. Recently, some Bt-endotoxin genes have been cloned in many different plants. Toxicological evaluations of three spore-crystal endotoxins, BtCry1Ia, BtCry10Aa and BtCry1Ba6 from B. thuringiensis, were carried out on mice to understand their adverse effects on hematological systems and on genetic material. These three spore-crystals have shown toxic activity to the boll weevil, which is one of the most aggressive pests of the cotton crop. Cry1Ia, Cry10Aa and Cry1Ba6 did not increase the micronucleus frequency in the peripheral erythrocytes of mice and did not cause changes in the frequency of polychromatic erythrocytes. However, some hematologic disburbances were observed, specifically related to Cry1Ia and Cry1Ba6, respectively, for the erythroid and lymphoid lineage. Thus, although the profile of such adverse side effects can be related to their high level of exposure, which is not commonly found in the environment, results showed that these Bt spore-crystals were not harmless to mice, indicating that each spore-crystal endotoxin presents a characteristic profile of toxicity and might be investigated individually. PMID:25268978

Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats.

PubMed

Reddy, M Kasi; Reddy, A Gopala; Kumar, B Kala; Madhuri, D; Boobalan, G; Reddy, M Anudeep

2017-01-01

The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN) in comparison to silymarin (SLM) against acetaminophen (APAP)-induced hepatotoxicity in rats. Male Wistar albino rats (n=24) of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity), and 15 (at the end of treatment). Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases) were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

Bleeding outcome during a dengue outbreak in 2005 in the East-coast region of Peninsular Malaysia: a prospective study.

PubMed

Fariz-Safhan, M N; Tee, H P; Abu Dzarr, G A; Sapari, S; Lee, Y Y

2014-06-01

During a dengue outbreak in 2005 in the East-coast region of Peninsular Malaysia, one of the worst hit areas in the country at that time, we undertook a prospective study. We aimed to describe the bleeding outcome and changes in the liver and hematologic profiles that were associated with major bleeding outcome during the outbreak. All suspected cases of dengue admitted into the only referral hospital in the region during the outbreak were screened for WHO 2002 criteria and serology. Liver function, hematologic profile and severity of bleeding outcome were carefully documented. The association between symptoms, liver and hematologic impairments with the type of dengue infection (classical vs. hemorrhagic) and bleeding outcome (major vs. non-major) was tested. Dengue fever was confirmed in 183 cases (12.5/100,000 population) and 144 cases were analysed. 59.7% were dengue hemorrhagic fever, 3.5% were dengue shock syndrome and there were 3 in-hospital deaths. Major bleeding outcome (gastrointestinal bleeding, intracranial bleeding or haemoptysis) was present in 14.6%. Elevated AST, ALT and bilirubin were associated with increasing severity of bleeding outcome (all P < 0.05). Platelet count and albumin level were inversely associated with increasing severity of bleeding outcome (both P < 0.001). With multivariable analysis, dengue hemorrhagic fever was more likely in the presence of abdominal pain (OR 1.1, 95% CI 0.02- 1.6) and elevated AST (OR 1.0, 95% CI 1.0-1.1) but the presence of pleural effusion (OR 5.8, 95% CI: 1.1-29.9) and elevated AST (OR 1.008, 95% CI: 1.005-1.01) predicted a severe bleeding outcome. As a conclusion, the common presence of a severe hemorrhagic form of dengue fever may explain the rising death toll in recent outbreaks and the worst impairment in liver and hematologic profiles was seen in major bleeding outcome.

Hematologic Complications of Pregnancy

PubMed Central

Townsley, Danielle M.

2013-01-01

Pregnancy induces a number of physiologic changes that affect the hematologic indices, either directly or indirectly. Recognizing and treating hematologic disorders that occur during pregnancy is difficult owing to the paucity of evidence available to guide consultants. This paper specifically reviews the diagnosis and management of benign hematologic disorders occurring during pregnancy. Anemia secondary to iron deficiency is the most frequent hematologic complication and is easily treated with oral iron formulations,; however care must be taken not to miss other causes of anemia, such as sickle cell disease. Thrombocytopenia is also a common reason for consulting the hematologist and distinguishing gestational thrombocytopenia from immune thrombocytopenia (ITP), preeclampsia, HELLP syndrome, or thrombotic thrombocytopenic purpura (TTP) is essential since the treatment differs widely. Occasionally the management of mother and infant involves the expeditious recognition of neonatal alloimmune thrombocytopenia (NAIT), a condition that is responsible for severe life-threatening bleeding of the newborn. Additionally, inherited and acquired bleeding disorders affect pregnant women disproportionately and often require careful monitoring of coagulation parameters in order to prevent bleeding in the puerperium. Finally, venous thromboembolism (VTE) during pregnancy is still largely responsible for mortality during pregnancy and the diagnosis, treatment options and guidelines for prevention of VTE during pregnancy are explored. PMID:23953339

A multiplex cytokine score for the prediction of disease severity in pediatric hematology/oncology patients with septic shock.

PubMed

Xu, Xiao-Jun; Tang, Yong-Min; Song, Hua; Yang, Shi-Long; Xu, Wei-Qun; Shi, Shu-Wen; Zhao, Ning; Liao, Chan

2013-11-01

Although many inflammatory cytokines are prognostic in sepsis, the utility of cytokines in evaluating disease severity in pediatric hematology/oncology patients with septic shock was rarely studied. On the other hand, a single particular cytokine is far from ideal in guiding therapeutic intervention, but combination of multiple biomarkers improves the accuracy. In this prospective observational study, 111 episodes of septic shock in pediatric hematology/oncology patients were enrolled from 2006 through 2012. Blood samples were taken for inflammatory cytokine measurement by cytometric bead array (CBA) technology at the initial onset of septic shock. Interleukin (IL)-6 and IL-10 were significantly elevated in majority of patients, while tumor necrosis factor (TNF)-α and interferon (IFN)-γ were markedly increased in patients with high pediatric index of mortality 2 (PIM2) score and non-survivors. All the four cytokines paralleled the PIM2 score and differentially correlated with hemodynamic disorder and fatal outcomes. The pediatric multiplex cytokine score (PMCS), which integrated the four cytokines into one score system, was related to hemodynamic disorder and mortality as well, but showed more powerful prediction ability than each of the four cytokines. PMCS was an independent predictive factor for fatal outcome, presenting similar discriminative power with PIM2, with accuracy of 0.83 (95% CI, 0.71-0.94). In conclusion, this study develops a cytokine scoring system based on CBA technique, which performs well in disease severity and fatality prediction in pediatric hematology/oncology patients with septic shock. Copyright © 2013 Elsevier Ltd. All rights reserved.

Microbiological and molecular identification of bacterial species isolated from nasal and oropharyngeal mucosa of fuel workers in Riyadh, Saudi Arabia.

PubMed

AlWakeel, Suaad S

2017-09-01

This study aimed to determine the bacterial species colonizing the nasal and oropharyngeal mucosa of fuel workers in Central Riyadh, Saudi Arabia on a microbiological and molecular level. Throat and nasal swab samples were obtained from 29 fuel station attendants in the period of time extending from March to May 2014 in Riyadh, Saudi Arabia. Microbiological identification techniques were utilized to identify the bacterial species isolated. Antibiotic sensitivity was assessed for each of the bacterial isolates. Molecular identification techniques based on PCR analysis of specific genomic sequences was conducted and was the basis on which phylogeny representation was done for 10 randomly selected samples of the isolates. Blood was drawn and a complete blood count was conducted to note the hematological indices for each of the study participants. Nineteen bacterial species were isolated from both the nasal cavity and the oropharynx including Streptococcus thoraltensis , alpha-hemolytic streptococci, Staphylococcus hominis , coagulase-negative staphylococci, Leuconostoc mesenteroides , Erysipelothrix rhusiopathiae and several others. We found 100% sensitivity of the isolates to ciprofloxacin, cefuroxime and gentamicin. Whereas cefotaxime and azithromycin posted sensitivities of 85.7% and 91.4%, respectively. Low sensitivities (<60% sensitivity) to the antibiotics ampicillin, erythromycin, clarithromycin and norfloxacin were observed. Ninety-seven percent similarity to the microbial bank species was noted when the isolates were compared to it. Most hematological indices recorded were within the normal range. In conclusion, exposure to toxic fumes and compounds within fuel products may be a contributing factor to bacterial colonization of the respiratory tract in fuel workers.

Treatment of Congenital Toxoplasmosis: Safety of the Sulfadoxine-Pyrimethamine Combination in Children Based on a Method of Causality Assessment.

PubMed

Teil, Julie; Dupont, Damien; Charpiat, Bruno; Corvaisier, Stéphane; Vial, Thierry; Leboucher, Gilles; Wallon, Martine; Peyron, François

2016-06-01

The treatment of newborns and infants with congenital toxoplasmosis is standard practice. Some observational studies have examined safety in newborns, but most of these failed to provide sufficient details for a provisional assessment of causality. The aim of this study was to evaluate the clinical and biological adverse effects of the combination of sulfadoxine-pyrimethamine. Sixty-five children treated for 1 year with a combination of sulfadoxine-pyrimethamine (1 dose every 10 days) for congenital toxoplasmosis were followed up to evaluate abnormal hematological values and potential adverse events using a standardized method of causality assessment. Nine patients (13.8%) presented at least 1 adverse clinical event that was nonspecific, such as diarrhea on the day of drug administration, vomiting and agitation. In 1 patient, erythema appeared at the end of the treatment and resolved within 10 days. None of these events was attributed to the treatment. Six patients (9.2%) developed an adverse hematological event (neutropenia, n = 3; eosinophilia, n = 2 and both anemia and eosinophilia, n = 1) that was considered to be possibly related to the sulfadoxine-pyrimethamine combination. Four treatments were temporarily interrupted, and toxicity was observed after readministration of treatment in 1 case only. However, none of these adverse events was life threatening. According to our results and previously published data, the combination of sulfadoxine-pyrimethamine seems to be well tolerated. However, the sample size of our study was too small to rule out the risk of less frequent, but nevertheless severe, reactions and, in particular, of hypersensitivity reactions.

In vivo toxic effects of 4-methoxy-5-hydroxy-canthin-6-one in zebrafish embryos via copper dyshomeostasis and oxidative stress.

PubMed

Gong, Guiyi; Jiang, Lingling; Lin, Qinghua; Liu, Wenyuan; He, Ming-Fang; Zhang, Jie; Feng, Feng; Qu, Wei; Xie, Ning

2018-01-01

Dysfunction of copper homeostasis can lead to a host of disorders, which might be toxic sometimes. 4-Methoxy-5-hydroxy-canthin-6-one (CAN) is one of the major constituents from Picrasma quassioides and responsible for its therapeutic effects. In this work, we evaluated the toxic effect of CAN (7.5μM) on zebrafish embryos. CAN treatment decreased survival, delayed hatching time and induced malformations (loss of pigmentation, pericardial edema, as well as hematologic and neurologic abnormalities). Besides, exogenous copper supplementation rescued the pigmentation and cardiovascular defects in CAN-treated embryos. Further spectroscopic studies revealed a copper-chelating activity of CAN. Then its regulation on the expressions of copper homeostasis related genes also be analyzed. In addition, CAN lowered the total activity of SOD, elevated the ROS production and altered the oxidative related genes transcriptions, which led to oxidative stress. In conclusion, we demonstrated that CAN (7.5μM) might exert its toxic effects in zebrafish embryos by causing copper dyshomeostasis and oxidative stress. It will give insight into the risk assessment and prevention of CAN-mediated toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute Oral Toxicity Evaluations of Some Zinc(II) Complexes Derived from 1-(2-Salicylaldiminoethyl)piperazine Schiff Bases in Rats

PubMed Central

Salga, Muhammad Saleh; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; Abdelwahab, Siddig Ibrahim

2012-01-01

The current study described the synthesis and the in vivo acute oral toxicity evaluations in Sprague Dawley rats. The compounds were characterized by elemental analyses, LC-MS, FTIR, 1H NMR, 13C NMR and UV-visible spectroscopy. In the acute toxicity study, a single administration of the compounds was performed orally to the rats at the single doses of 2000 mg/kg and they were then monitored for possible side effects, mortality or behavioral changes up to 14 days. The serum level of aspartate (AST), alanine aminotransferases (ALT), alkaline phosphate (ALP), triglyceride, high density lipoprotein (HDL), immunoglobulins (GAM) and the C-reactive proteins did not significantly change. The hematological indices white blood cells (WBC), haematocrit (HCT), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH) were within the normal range. The renal function indices examined were also within the reference range. Generally, the compounds exhibited low toxic effects as required for further in vivo therapeutic studies. PMID:22408397

Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate.

PubMed

Choi, Yun Jung; Park, Hyangmin; Lee, Ji Sung; Lee, Ju-Yeon; Kim, Shin; Kim, Tae Won; Park, Jung Sun; Kim, Jeong Eun; Yoon, Dok Hyun; Suh, Cheolwon

2017-12-01

The genetic association of the methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism with methotrexate (MTX)-associated toxicity has been evaluated and conflicting results have been reported. The substantial heterogeneity of the studied population was suggested to be a possible explanation because ethnicity, MTX dose, coadministered chemotherapeutic agents, and folinate rescue dosage regimen could alter the MTX toxicity profile. The patient population was homogenized by limiting the cancer type to primary central nervous system lymphoma and chemotherapy protocol to a high-dose MTX monotherapy regimen. A total of 111 patients with 402 chemotherapy courses were analyzed. MTHFR 677C>T polymorphism was identified as an independent predictive marker for MTX-associated hematologic toxicity (odds ratio, 2.60; 95% confidence interval, 1.32-5.09; P = .0055). Clinically significant nephrotoxicity occurred in patients without delayed elimination, suggesting roles for factors other than serum MTX levels. MTX-induced hepatotoxicity and oral mucositis occurred independently of plasma MTX levels. Copyright © 2016 John Wiley & Sons, Ltd.

Morphological and hematological studies of Trypanosoma spp. infecting ornamental armored catfish from Guamá River-PA, Brazil.

PubMed

Fujimoto, Rodrigo Y; Neves, Mikaelle S; Santos, Rudã F B; Souza, Natalino C; Do Couto, Márcia V S; Lopes, Josiane N S; Diniz, Daniel G; Eiras, Jorge C

2013-09-01

A total of 281 specimens of freshwater armored ornamental fish species (Leporacanthicus galaxias,Lasiancistrus saetiger, Cochliodon sp., Hypostomus sp., Pseudacanthicus spinosus, Ancistrus sp. and Rineloricaria cf. lanceolata) were captured at the hydrological basin of Guamá River, Pará, Brazil. The infection by Trypanosoma spp. was inspected. The morphological and morphometric characterization of the parasites and the hematological parameters were determined. Leporacanthicus galaxias and Pseudacanthicus spinosus presented 100% infection prevalence, and the other species showed a variable prevalence of infection. The parasites showed clearly different morphotypes and dimensions, and probably belong to different species. The hematological response to the infection varied with the host. Cochliodon sp. showed no differences between infected and not infected fish. In other species several modifications on some hematological parameters were found, but apparently without causing disease. It is emphasized the possibility of introduction of the parasites in new environments due to the artificial movements of these ornamental fish.

[Hematological changes in adolescent anorexia nervosa].

PubMed

Bühren, Katharina; Gärtner, Laura; Kennes, Lieven N; Seitz, Jochen; Hagenah, Ulrich; Herpertz-Dahlmann, Beate

2014-01-01

Hematological changes often occur in patients with acute anorexia nervosa (AN). However, the relationship between these disturbances and other clinical parameters remains unclear. Leucocyte, erythrocyte, and thrombocyte counts as well as hematocrit, hemoglobin, and differential blood counts were collected at admission and after weight restoration in 88 female adolescent patients with the diagnosis of AN according to DSM-IV. These were then compared to clinical parameters. At admission, there were mild changes in the blood count, most of which, however, were reversible after weight gain. Patients with a greater weight loss, a lower age-adjusted BMI, and a history of taking psychotropic drugs were more likely to develop hematological abnormalities. Although most of the hematological changes in adolescent patients with AN were mild, patients with high weight loss and/or low age-adjusted BMI as well as those on psychotropic medication should be monitored carefully in order to avoid severe medical complications. An altered immune function in adult patients with chronic AN might contribute to a higher rate of infections and thus to an increased mortality.

Acute and Subacute toxicity study of Olaquindox by feeding to common carp (Cyprinus carpio L.).

PubMed

Yang, Qian; He, Jie; He, Sheng-Yu; Wang, Kai-Yu; Geng, Yi; Chen, De-Fang; Huang, Xiao-Li; Ou-Yang, Ping

2018-06-08

Olaquindox, is a growth-promoting feed additive for food-producing animals. As the banned medicinal feed additive, olaquindox in animal feed and water must be concerned as an important hazard index. To improve studies of the toxicity of olaquindox, we provide a toxicological effects of olaquindox on a common freshwater fish, Cyprinus carpio L. The results of acute toxicity tests showed that the 7d-LD 50 of olaquindox administered by feeding for common carp was determined to be 3746.3 mg/kg. We also found that the accumulation coefficient of olaquindox in carp was 1.45-1.9. Based on the studied hematological and blood biochemical parameters (RBCs count, hemoglobin content, ALT, AST and SOD activity), we found that olaquindox induced significant alterations in all studied parameters. Regarding bioaccumulation, the results showed that olaquindox had more efficiency to internalize fish tissues (liver, kidneys and muscle). The histopathological investigation of tissues from poisoning fish revealed various alterations that varied between adaptation responses and permanent tissue damage. Our results indicate that olaquindox are toxic to common carp and have obvious accumulation, and all the data from acute and subacute toxicity experiments in common carp may provide a useful tool for assessing the toxicity of olaquindox to aquatic organisms. Copyright © 2018 Elsevier Inc. All rights reserved.

Absence of subchronic oral toxicity and genotoxicity of rice koji with Aspergillus terreus.

PubMed

Yun, Jun-Won; Kim, Seung-Hyun; Kim, Yun-Soon; You, Ji-Ran; Cho, Eun-Young; Yoon, Jung-Hee; Kwon, Euna; Lee, Sang Ju; Kim, Seong Pil; Seo, Jae Hoon; In, Jae Pyung; Ahn, Jae Hun; Jang, Ja-June; Park, Jin-Sung; Che, Jeong-Hwan; Kang, Byeong-Cheol

2017-10-01

Koji products have been considered as an effective fermented food consumed in East Asia with many health benefits. Particularly, rice koji with Aspergillus terreus (RAT) has been reported to be able to prevent hyperlipidemia and hepatic steatosis through regulating cholesterol synthesis. Despite its biological activities, there is a lack of comprehensive information to give an assurance of its safety. Therefore, the objective of this study was to perform a series of toxicological studies (repeated dose oral toxicity and genotoxicity) according to test guidelines published by the Organization for Economic Cooperation and Development. Along with acute toxicity study using rats and beagle dogs, a 13-week toxicity study revealed no clear RAT-related toxic changes, including body weight, mortality, hematology, serum biochemistry, organ weight, and histopathology after oral administration at doses of 500, 1000, and 2000 mg/kg BW. The no-observed-adverse-effect level of RAT was considered to be more than 2000 mg/kg BW/day in rats of both genders. In addition, potential genotoxicity was evaluated using a standard battery of tests (Ames test, chromosome aberration assay, and micronucleus assay) which revealed that RAT showed no genotoxicity. Accordingly, these results suggest that RAT is a safe and non-toxic functional food for human consumption at proper dose. Copyright © 2017. Published by Elsevier Inc.

Subchronic (13-week) oral toxicity study of dihomo-gamma-linolenic acid (DGLA) oil in rats.

PubMed

Kawashima, Hiroshi; Toyoda-Ono, Yoshiko; Suwa, Yoshihide; Kiso, Yoshinobu

2009-06-01

Dihomo-gamma-linolenic acid (DGLA) is one of the essential fatty acids, and has anti-inflammatory and anti-allergic effects. To assess the toxicity of a novel DGLA oil produced by the fungus Mortierella alpina, we examined it in the Ames test and in acute and subchronic oral toxicity tests in rats. In the Ames test, no mutagenicity was found up to 5000 microg/plate. The acute toxicity test revealed no toxicity related to DGLA oil at 10 g/kg. In the subchronic toxicity test, DGLA oil (500, 1000, and 2000 mg/kg) was orally administered. Water and soybean oil (2000 mg/kg) were used for the no-oil control and soybean oil control groups, respectively. There was no death in either sex. Because of administration of large amounts of oil, food consumption was low in the soybean oil control and the three test groups, which appeared to mildly decrease urinary excretion of Na, K, and Cl, as well as total serum protein, albumin, and blood urea nitrogen levels. There were no toxicological changes in body weight, food consumption, ophthalmological examination, urinalysis, hematological examination, blood biochemical examination, necropsy, organ weight, or histopathological examination. These findings show that the no-observed-adverse-effect level of the DGLA oil was 2000 mg/kg.

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg(-1) for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg(-1) of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender.

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed Central

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg−1 for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg−1 of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender. PMID:24369482

Prevention and treatment of Nitrite toxicity in juvenile steelhead trout (Salmo gairdneri)

USGS Publications Warehouse

Wedemeyer, Gary A.; Yasutake, W.T.

1978-01-01

The efficacy of mineral salts, pH, and tetramethylthianine (methylene blue) treatment in reducing the acute toxicity of nitrite to fingerling steelhead trout (Salmo gairdneri) was determined using a static bioassay system at 10 °C. The acute toxicity (96-h LC50) was reduced by a factor of about 24 for 5-g steelhead and 13 for 10-g fish when the total water hardness was increased from 25 to 300 mg/L (as CaCO3). NaCl or CaCl2 additions (0–200 mg/L) reduced toxicity by a factor of up to 3 for NaCl and 50 for CaCl2. Increasing the pH from 6.0 to 8.0 decreased toxicity by a factor of about 8 for the smaller and 3 for the larger fish. Methylene blue at 0.1 or 1.0 mg/L was effective in decreasing acute toxicity. For alleviating methemoglobinemia, removing the fish to freshwater for 48 h was about as effective as 1.0 mg/L methylene blue. Chronic exposure in soft water to 0.03 mg/L NO2-N for 6 mo caused no significant growth reduction, gill histological changes, hematological dyscrasias, or impaired ability of the smolts to adapt to 30‰ seawater and grow for an additional 2 mo. Key words: nitrite, toxicity, fish, methylene blue, pH, salts, acute toxicity, chronic toxicity

Fourteen-Day Subchronic Oral Toxicity Study of 4-Nitrophenyl Methyl (Phenyl) Phosphinate in Male and Female Rats.

DTIC Science & Technology

1982-09-01

gavage for 14 days. Neb±rops les and histological examinations were performed on all animals. Urinalysis, standard hematological measurements and an...activity. The only compound related effects found in the histological examinations were gross changes in the digestive system in one or more male rats at...rats (1/2, 1/4, 1/8, and 1/16 of the LD^) were used. Rats were dosed daily by gastric gavage for 14 dayg. Necropsies and histological examinations gire

Six Month Oral Toxicity Study of WR238605 Succinate in Rats. Volume 1

DTIC Science & Technology

1996-02-02

expressed on the basis of mg base/kg/day. Statistical analyses was performed on an IBM • compatible computer using the commercially available LabCat... iTP (F) tA/G *BUN tTBA(M/F?) Hematology1 NE *RBC(F) iHCT(F) *HGB(F) tMETHGB *PLT(M) i RBC...1 A-2 Part 1: Identity, Purity and Stability of Neat WR238605 Succinate 0bjttaTO IBM ! The objective of this study was to confirm the identity and

Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination with Docetaxel

DTIC Science & Technology

2008-10-01

for > 3 platelet transfusion in 30 days • Gr 4 neutropenia • Febrile neutropenia • Attributable Gr > 3 non-hematologic toxicity (excluding infusion...0% No febrile neutropenia (no growth factor use) • Transaminitis (n=12 evaluable) Transient Gr 1 17% (no Gr > 1) Figure-1...therapies and 36% progressed on 1-4 lines of chemotherapy including docetaxel. No DLT’s have been seen. 2 pts experienced reversible Gr 3 neutropenia

Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants.

PubMed

Strober, Samuel

2016-03-24

The goals of tolerance in patients with solid organ transplants are to eliminate the lifelong need for immunosuppressive (IS) drugs and to prevent graft loss due to rejection or drug toxicity. Tolerance with complete withdrawal of IS drugs has been achieved in recipients of HLA-matched and mismatched living donor kidney transplants in 3 medical centers using hematopoietic cell transplants to establish mixed or complete chimerism. © 2016 by The American Society of Hematology.

Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Stephenson, Matthew D; Bowen, Joanne M; Keefe, Dorothy M; Peters, Micah D J

2016-07-01

Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

Profile and scientific production of the Brazilian Council for Scientific and Technological Development (CNPq) researchers in the field of Hematology/Oncology.

PubMed

Oliveira, Maria Christina Lopes Araujo; Martelli, Daniella Reis; Quirino, Isabel Gomes; Colosimo, Enrico Antônio; Silva, Ana Cristina Simões e; Martelli Júnior, Hercílio; Oliveira, Eduardo Araujo de

2014-01-01

several studies have examined the academic production of the researchers at the CNPq, in several areas of knowledge. The aim of this study was to evaluate the scientific production of researchers in Hematology/Oncology who hold scientific productivity grants from the Brazilian Council for Scientific and Technological Development. the Academic CVs of 28 researchers in Hematology/Oncology with active grants in the three-year period from 2006 to 2008 were included in the analysis. The variables of interest were: institution, researchers' time after doctorate, tutoring of undergraduate students, masters and PhD degree, scientific production and its impact. from a total of 411 researchers in Medicine, 28 (7%) were identified as being in the area of Hematology/Oncology. There was a slight predominance of males (53.6%) and grant holders in category 1. Three Brazilian states are responsible for approximately 90% of the researchers: São Paulo (21,75%), Rio de Janeiro (3,11%), and Minas Gerais (2, 7%). During their academic careers, the researchers published 2,655 articles, with a median of 87 articles per researcher (IQR = 52 to 122). 65 and 78% of this total were indexed on the Web of Science and Scopus databases, respectively. The researchers received 14,247 citations on the WoS database with a median of 385 citations per researcher. The average number of citations per article was 8.2. in this investigation, it was noted that researchers in the field of Hematology/Oncology have a relevant scientific output from the point of view of quantity and quality compared to other medical specialties.

Hematology and serum biochemistry in debilitated, free-ranging raccoon dogs (Nyctereutes procyonoides) infested with sarcoptic mange.

PubMed

Kido, Nobuhide; Kamegaya, Chihiro; Omiya, Tomoko; Wada, Yuko; Takahashi, Maya; Yamamoto, Yasuhiko

2011-12-01

Frequent outbreaks of Sarcoptes scabiei infestation in raccoon dogs (Nyctereutes procyonoides) have been reported in Japan. Although many raccoon dogs are brought to Kanazawa Zoological Garden (Yokohama, Kanagawa, Japan) because of S. scabiei infestation and debilitation, some of them die of asthenia. The clinical status of severely debilitated raccoon dogs must be determined to save their lives. In this study, we compared hematological and serum biochemical values between severely debilitated and nondebilitated raccoon dogs infested with S. scabiei. The total protein, albumin, glucose, and calcium values of debilitated raccoon dogs were significantly lower than those of nondebilitated raccoon dogs. On the other hand, debilitated raccoon dogs had significantly higher aspartate aminotransferase, total bilirubin, blood urea nitrogen, sodium, chloride, and phosphorus values than did nondebilitated raccoon dogs. The increase in the blood urea nitrogen value was particularly dramatic. The present study revealed that debilitated raccoon dogs infested with S. scabiei exhibited abnormal hematological values compared with nondebilitated raccoon dogs infested with S. scabiei. Clinically, the raccoon dogs developed malnutrition and sepsis if the mange infestation was untreated. Moreover, dehydration associated with appetite loss may have resulted in insufficient renal perfusion. These findings suggest that chronic S. scabiei infestations debilitated the raccoon dogs and resulted in physiological changes that were detected with hematological and serum biochemical tests. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Newman, Neil B.; Sidhu, Manpreet K.; Baby, Rekha

Purpose/Objective(s): To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. Methods and Materials: We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressionsmore » evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. Results: During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. Conclusions: Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.« less

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy.

PubMed

Newman, Neil B; Sidhu, Manpreet K; Baby, Rekha; Moss, Rebecca A; Nissenblatt, Michael J; Chen, Ting; Lu, Shou-En; Jabbour, Salma K

2016-04-01

To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers.

PubMed

Imhof, Anna; Brunner, Philippe; Marincek, Nicolas; Briel, Matthias; Schindler, Christian; Rasch, Helmut; Mäcke, Helmut R; Rochlitz, Christoph; Müller-Brand, Jan; Walter, Martin A

2011-06-10

To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers. In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [(90)Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface [(90)Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. Overall, 1,109 patients received 2,472 cycles of [(90)Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003). This study documents the long-term outcome of [(90)Y-DOTA]-TOC treatment in a large cohort. Response to [(90)Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [(90)Y-DOTA]-TOC treatment and occurrence of renal toxicity.

Ipilimumab for Patients with Relapse after Allogeneic Transplantation

PubMed Central

Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Costello, Caitlin; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Avigan, David; Chen, Yi-Bin; McSweeney, Peter; LeBoeuf, Nicole R.; Rooney, Michael S.; Bowden, Michaela; Zhou, Chensheng W.; Granter, Scott R.; Hornick, Jason L.; Rodig, Scott J.; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Streicher, Howard; Ball, Edward D.; Ritz, Jerome; Bashey, Asad; Soiffer, Robert J.

2016-01-01

BACKGROUND Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte–associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.) PMID:27410923

From Infancy to Adolescence: Fifteen Years of Continuous Treatment With Hydroxyurea in Sickle Cell Anemia

PubMed Central

Hankins, Jane S.; Aygun, Banu; Nottage, Kerri; Thornburg, Courtney; Smeltzer, Matthew P.; Ware, Russell E.; Wang, Winfred C.

2014-01-01

Abstract Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5–31.2); neutropenia [absolute neutrophil count (ANC) < 1.0 × 109/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC < 0.5 × 109/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10–14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10–12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA. PMID:25526439

From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia.

PubMed

Hankins, Jane S; Aygun, Banu; Nottage, Kerri; Thornburg, Courtney; Smeltzer, Matthew P; Ware, Russell E; Wang, Winfred C

2014-12-01

Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA.

Pre-clinical toxicity of a combination of berberine and 5-aminosalicylic acid in mice.

PubMed

Li, Yan-Hong; Zhang, Man; Fu, Hai-Bo; Xiao, Hai-Tao; Bian, Zhao-Xiang

2016-11-01

Our previous study demonstrated that a combination of alternative medicine berberine and conventional 5-aminosalicylic acid (5-ASA) showed promise to be a novel therapeutic strategy for ulcerative colitis (UC). This present study aims to sketch the pre-clinical toxicity profile of this combination (1:10 dose ratio) on mice. In acute toxicity test, the determined median lethal dose (LD 50 ) was 278.7 mg/kg berberine plus 2787 mg/kg 5-ASA. The results from subacute toxicity test demonstrated that no toxic signs of clinical symptoms, no significant changes in hematological or biochemical parameters were detected in mice treated with 14 + 140, 28 + 280 or 56 + 560 mg/kg of berberine plus 5-ASA treatment. Histological examinations revealed that accompanied with an increase in spleen weight, frequently recorded enlargement and white pulp hyperplasia of spleen were detected in mice when exposed to three doses of combination treatments. Further in vitro assessment suggested that the spleen toxicity was originated from berberine by its inhibition in cell viability and cell proliferation of lymphocytes. The results of this study indicate that the combination of berberine and 5-ASA shows a slight toxic effect on spleen, suggesting that this combination should be used with caution for patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute and subacute toxicity of Schinus terebinthifolius bark extract.

PubMed

Lima, L B; Vasconcelos, C F B; Maranhão, H M L; Leite, V R; Ferreira, P A; Andrade, B A; Araújo, E L; Xavier, H S; Lafayette, S S L; Wanderley, A G

2009-12-10

Schinus terebinthifolius Raddi (Anacardiaceae) has long been used in traditional Brazilian medicine, especially to treat inflammatory and haemostatic diseases. The objective of this study was to evaluate the acute and subacute toxicity (45 days) of Schinus terebinthifolius via the oral route in Wistar rats of both sexes. For the acute toxicity test, the dried extract of Schinus terebinthifolius bark was administered in doses from 0.625 to 5.0 g/kg (n=5/group/sex) and in the subacute toxicity test the following doses were used: 0.25, 0.625 and 1.5625 g/kg/day (n=13/group/sex), for 45 consecutive days. In the acute toxicity test, Schinus terebinthifolius did not produce any toxic signs or deaths. The subacute treatment with Schinus terebinthifolius did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups, except in two male groups, in which the treatment with Schinus terebinthifolius (0.25 and 0.625 g/kg) induced an increase of mean corpuscular volume values (2.9 and 2.6%, respectively). These variations are within the physiological limits described for the specie and does not have clinical relevance. The acute and subacute administration of the dried extract of Schinus terebinthifolius bark did not produced toxic effects in Wistar rats.

Adverse hematological effects of hexavalent chromium: an overview

PubMed Central

2016-01-01

Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders. PMID:28652847

Adverse hematological effects of hexavalent chromium: an overview.

PubMed

Ray, Rina Rani

2016-06-01

Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca 2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders.

Managing critically Ill hematology patients: Time to think differently.

PubMed

Azoulay, Elie; Pène, Frédéric; Darmon, Michael; Lengliné, Etienne; Benoit, Dominique; Soares, Marcio; Vincent, Francois; Bruneel, Fabrice; Perez, Pierre; Lemiale, Virginie; Mokart, Djamel

2015-11-01

The number of patients living with hematological malignancies (HMs) has increased steadily over time. This is the result of intensive and effective treatments that also increase the probability of infiltrative, infectious or toxic life threatening event. Over the last two decades, the number of patients with HMs admitted to the ICU increased and their mortality has dropped sharply. ICU patients with HMs require an extensive diagnostic workup and the optimal use of ICU treatments to identify the reason for ICU admission and the nature of the complication that explains organ dysfunctions. Mortality of ARDS or septic shock is up to 50%, respectively. In this review, the authors share their experience with managing critically ill patients with HMs. They discuss the main aspects of the diagnostic and therapeutic management of critically ill patients with HMs and argue that outcomes have improved over time and that many classic determinants of mortality have become irrelevant. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chimeric Antigen Receptor T Cells and Hematopoietic Cell Transplantation: How Not to Put the CART Before the Horse.

PubMed

Kenderian, Saad S; Porter, David L; Gill, Saar

2017-02-01

Hematopoietic cell transplantation (HCT) remains an important and potentially curative option for most hematologic malignancies. As a form of immunotherapy, allogeneic HCT (allo-HCT) offers the potential for durable remissions but is limited by transplantation- related morbidity and mortality owing to organ toxicity, infection, and graft-versus-host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematologic malignancies as well. Clinical trials are now needed to address the relative roles of CART cells and HCT in the context of transplantation-eligible patients. In this review, we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma, and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles.

PubMed

Venkatasubbu, Gopinath Devanand; Ramasamy, S; Gaddam, Pramod Reddy; Kumar, J

2015-01-01

Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile.

Immunotoxin – a new treatment option in patients with relapsed and refractory Hodgkin lymphoma

PubMed Central

Novakovic, Barbara Jezersek

2015-01-01

Background Even though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT) and autologous hematopoietic cell rescue (SCT). On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options. Conclusions A new treatment option in this population is an immunotoxin Brentuximab vedotin composed of a CD30 directed antibody linked to the antitubulin agent monomethyl auristatin E. It has demonstrated a substantial effectiveness and an acceptable toxicity. In the pivotal study, the overall response rate was 75% with 34% of complete remissions. The median durations of response were 20.5 and 6.7 months for those with complete remission and all responding patients, respectively. The median overall survival was 40.5 months (3-years overall survival 54%) and the median progression-free survival 9.3 months. The most common non-hematologic toxicities were peripheral sensory neuropathy, nausea, and fatigue while the most common severe side effects were neutropenia, thrombocytopenia, anemia, and peripheral sensory neuropathy. PMID:26834516

[Genetic polymorphisms of thiopurine methyltransferase and incidence of adverse events in patients with medical indication of azathioprine].

PubMed

Buhl, Manuel A; Gómez, Graciela; Collado, María Victoria; Oddo, Elisabet M; Khoury, Marina; Azurmendi, Pablo J; Sarano, Judith

2018-01-01

Azathioprine is a thiopurine which has a narrow therapeutic index and marked hematological and hepatic toxicity. Thiopurine s-methyltransferase is an enzyme involved in the metabolism of thiopurines. Mutations in the gene that encodes the enzyme may augment the risk of adverse events. For that reason, pharmacogenetic determinations prior to the initiation of therapy can provide useful information for the future therapeutic strategy. Nevertheless, its utility in the local environment is not completely established. Forty-five subjects (13 men) who had been prescribed azathioprine were included. The presence of *2, *3A, *3B and *3C mutations were determined by PCR-RFLP, and the relationship between genotype and incidence of adverse events related to the drug was analyzed. Nine carried at least one non-functional allele, one of them with *3A/*3A genotype. Among the eighteen patients who initiated treatment with azathioprine, toxicity was detected in 3 cases: 2 mild events were observed in patients with normal genotype, and the only serious event (bone marrow suppression) occurred in the individual with homozygous mutant genotype. The only homozygous mutant patient developed the most severe of the registered events, in spite of being under treatment with low doses of azathioprine. This is the reason why enzymatic determination could be of utility, even though it does not replace clinical and biochemical follow-up in patients under thiopurine treatment.

Systemic gemcitabine combined with intra-arterial low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma: Seven cases

PubMed Central

Uka, Kiminori; Aikata, Hiroshi; Takaki, Shintaro; Kawaoka, Tomokazu; Saneto, Hiromi; Miki, Daiki; Takahashi, Shoichi; Toyota, Naoyuki; Ito, Katsuhide; Chayama, Kazuaki

2008-01-01

The combination of intra-arterial low-dose cisplatin and 5-fluorouracil (5-FU) is effective against advanced hepatocellular carcinoma (HCC). Systemic gemcitabine chemotherapy seems effective in many cancers. We report the results of combination therapy with systemic gemcitabine, intra-arterial low-dose cisplatin and 5-FU (GEMFP). Seven patients with non-resectable advanced HCC were treated with GEMFP. One course of chemotherapy consisted of daily intra-arterial cisplatin (20 mg/body weight/hour on d 1, 10 mg/body weight per 0.5 h on d 2-5 and 8-12), followed by 5-FU (250 mg/body weight per 5 h on d 1-5 and 8-12) via an injection port. Gemcitabine at 1000 mg/m2 was administered intravenously at 0.5 h on d 1 and 8. The objective response was 57%. The response to GEMFP was as follows: complete response (no patients), partial response (four patients), stable disease (three patients), and progressive disease (no patients). The median survival period was 8 mo (range, 5-55). With regard to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 adverse reactions, seven (100%), seven, six (86%) and one (14%) patients developed leukopenia, neutropenia, thrombocytopenia and anemia, respectively. GEMFP may potentially be effective for non-resectable advanced HCC, but it has severe hematologic toxicity. PMID:18442216

Non-viral RNA chimeric antigen receptor modified T cells in patients with Hodgkin lymphoma.

PubMed

Svoboda, Jakub; Rheingold, Susan R; Gill, Saar I; Grupp, Stephan A; Lacey, Simon F; Kulikovskaya, Irina; Suhoski, Megan M; Melenhorst, J Joseph; Loudon, Brandon; Mato, Anthony R; Nasta, Sunita Dwivedy; Landsburg, Daniel J; Youngman, Matthew R; Levine, Bruce L; Porter, David L; June, Carl H; Schuster, Stephen J

2018-06-20

Chimeric antigen receptor (CAR) modified T cells are being investigated in many settings including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS. We hypothesized that eradicating CD19 positive (+) B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19 directed CAR modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed and refractory cHL. To limit potential toxicities, we used non-viral RNA CART19 cells which are expected to express CAR protein only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of non-viral RNA CART19 and 4 were infused with protocol specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use non-viral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as NCT02277522 (adult) and NCT02624258 (pediatric). Copyright © 2018 American Society of Hematology.

Endothelial and circulating progenitor cells in hematological diseases and allogeneic hematopoietic stem cell transplantation.

PubMed

Ruggeri, Annalisa; Paviglianiti, Annalisa; Volt, Fernanda; Kenzey, Chantal; Rafii, Hanadi; Rocha, Vanderson; Gluckman, Eliane

2017-10-12

Circulating endothelial cells (CECs), originated form endothelial progenitors (EPCs) are mature cells which are not associated with vessel walls, and that are detached from the endothelium. Normally, they are present in insignificant amounts in the peripheral blood of healthy individuals. On the other hand, elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and some other diseases. Consequently, CECs and EPCs represent a potential biomarker in several clinical conditions involving endothelial turnover and remodeling, such as hematological diseases. These cells may be involved in disease progression and the neoplastic angiogenesis process. Moreover, CESs and EPCs are probably involved in endothelial damage that is a marker of several complications following allogeneic hematopoietic stem cell transplantation. This review aims to provide an overview on the characterization of CECs and EPCs, describe isolation methods and to identify the potential role of these cells in hematological diseases and hematopoietic stem cell transplantation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

LPG Dependence after a Suicide Attempt

PubMed Central

Aldemir, Ebru; Akyel, Betül; Altıntoprak, A. Ender; Aydın, Rezzan; Coşkunol, Hakan

2015-01-01

Inhalant abuse is a problem that is getting more common all around the world. The increase in prevalence of inhalant abuse escalates morbidity and mortality rates. About 22% of people using inhalant have died at their first attempt. Particularly propane, butane, or propane-butane mixture has highest mortality rates. Sudden sniffing death syndrome, cardiomyopathy, central nervous system toxicity, hematological abnormalities, kidney toxicity, and hepatocellular toxicities are the major complications of inhalant abuse. Herein we present a patient with inhalant use disorder. At the age of 19, after a stressful life event he had unsuccessfully tried to suicide by inhaling LPG (liquefied petroleum gas, a mixture of butane and propane gases). After he realized that he had hallucinations and felt better during the inhalation, he started to abuse it. He was addicted to LPG for 10 years at the time of admission. Besides being dangerous for the society security, this intense level of LPG inhalation (12 liters a day) not giving any physical harm makes this case interesting. PMID:25664196

Transplantation for myelodysplastic syndromes: who, when, and which conditioning regimens.

PubMed

Saber, Wael; Horowitz, Mary M

2016-12-02

Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Broad application is hindered by high risks of transplant-related morbidity and mortality, especially in the older age range represented by the MDS population. However, recent advances in strategies to minimize regimen-related toxicity make HCT a viable option for many more patients. Appropriate selection of patients involves consideration of patient factors, including use of geriatric assessment tools and comorbidity scales, that predict risks of regimen-related toxicity as well as disease factors, including genetic markers, which predict survival with both non-HCT and HCT therapy. Optimal timing of HCT for fit patients must consider MDS risk scores and life-years to be gained, with earlier transplantation indicated for patients with intermediate-2 and high-risk disease but judicious delay for lower risk patients. Selection of suitable conditioning regimens must balance risks of toxicity with opportunity for maximum disease control. © 2016 by The American Society of Hematology. All rights reserved.

Toxicological evaluation of Cladophora glomerata Kützing and Microspora floccosa Thuret in albino rats.

PubMed

Fahprathanchai, Prannapus; Saenphet, Kanokporn; Peerapornpisal, Yuwadee; Aritajat, Salika

2006-01-01

This study aimed to evaluate the toxicity of Cladophora glomerata and Microspora floccosa ethanolic extracts in rats. Acute toxicity was tested with a single oral administration of the extract at a dose of 25 g/kg bd wt. Mortality, behavior, amount of food intake, body weight, and any abnormalities of the visceral organs, were observed. The results showed that the extract caused neither mortality, nor abnormalities. Subchronic toxicity was tested by administering the extract at doses of 0.5 g/kg and 1.0 g/kg for 60 days. Differences in body weight, hematology and blood biochemistry (alanine aminotransferase, ALT; aspartate aminotransferase, AST; blood urea nitrogen, BUN and creatinine, Cre) were not detected among the control and treatment groups. Although the packed cell volume of the male rats treated with 1.0 g/kg extract was significantly lower than the controls (p< or =0.05), the level was in the standard range for rat hematocrit.

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma.

PubMed

Mark, Tomer M; Bowman, Isaac A; Rossi, Adriana C; Shah, Manan; Rodriguez, Melissa; Quinn, Ryann; Pearse, Roger N; Zafar, Faiza; Pekle, Karen; Jayabalan, David; Ely, Scott; Coleman, Morton; Chen-Kiang, Selina; Niesvizky, Ruben

2014-12-01

We studied T-BiRD (thalidomide [Thalomid(®)], clarithromycin [Biaxin(®)], lenalidomide [Revlimid(®)] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1-28; lenalidomide 25 mg/day on days 1-21; and thalidomide 100 mg/day (50 mg/day on days 1-7 of cycle 1 only) on days 1-28. Twenty-six patients received a median of 6 cycles (range 0-41). Overall response rate (ORR) was 80% for the group and 100% in 11 patients who underwent autologous stem cell transplantation as part of first-line therapy. The 4-year overall survival rate was 74.9%, and the median progression-free survival was 35.6 months. Eight patients discontinued due to regimen toxicity. Grade 3 non hematologic toxicity affected 12 patients (46.2%). T-BiRD is a highly active regimen with potential toxicity limitations. ClinicalTrials.gov identifier: NCT00538733.

Environmental Mercury and Its Toxic Effects

PubMed Central

Rice, Kevin M.; Walker, Ernest M.; Wu, Miaozong; Gillette, Chris

2014-01-01

Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the amount of atmospheric mercury, which enters the atmospheric-soil-water distribution cycles where it can remain in circulation for years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating contaminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic pathophysiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects. PMID:24744824

LPG Dependence after a Suicide Attempt.

PubMed

Aldemir, Ebru; Akyel, Betül; Altıntoprak, A Ender; Aydın, Rezzan; Coşkunol, Hakan

2015-01-01

Inhalant abuse is a problem that is getting more common all around the world. The increase in prevalence of inhalant abuse escalates morbidity and mortality rates. About 22% of people using inhalant have died at their first attempt. Particularly propane, butane, or propane-butane mixture has highest mortality rates. Sudden sniffing death syndrome, cardiomyopathy, central nervous system toxicity, hematological abnormalities, kidney toxicity, and hepatocellular toxicities are the major complications of inhalant abuse. Herein we present a patient with inhalant use disorder. At the age of 19, after a stressful life event he had unsuccessfully tried to suicide by inhaling LPG (liquefied petroleum gas, a mixture of butane and propane gases). After he realized that he had hallucinations and felt better during the inhalation, he started to abuse it. He was addicted to LPG for 10 years at the time of admission. Besides being dangerous for the society security, this intense level of LPG inhalation (12 liters a day) not giving any physical harm makes this case interesting.

Multidrug-resistant bacteria in hematology patients: emerging threats.

PubMed

Tatarelli, Paola; Mikulska, Malgorzata

2016-06-01

Multidrug-resistant (MDR) bacteria, particularly Gram negatives, such as Enterobacteriaceae resistant to third-generation cephalosporins or carbapenems and MDR Pseudomonas aeruginosa, are increasingly frequent in hematology patients. The prevalence of different resistant species varies significantly between centers. Thus, the knowledge of local epidemiology is mandatory for deciding the most appr-opriate management protocols. In the era of increasing antibiotic resistance, empirical therapy of febrile neutropenia should be individualized. A de-escalation approach is recommended in case of severe clinical presentation in patients who are at high risk for infection with a resistant strain. Targeted therapy of an MDR Gram negative usually calls for a combination treatment, although no large randomized trials exist in this setting. Infection control measures are the cornerstone of limiting the spread of MDR pathogens in hematology units.

Hematologic complications of pregnancy.

PubMed

Townsley, Danielle M

2013-07-01

Pregnancy induces a number of physiologic changes that affect the hematologic indices, either directly or indirectly. Recognizing and treating hematologic disorders that occur during pregnancy is difficult owing to the paucity of evidence available to guide consultants. This review discusses specifically the diagnosis and management of benign hematologic disorders occurring during pregnancy. Anemia secondary to iron deficiency is the most frequent hematologic complication and is easily treated with oral iron formulations; however, care must be taken not to miss other causes of anemia, such as sickle cell disease. Thrombocytopenia is also a common reason for consulting the hematologist, and distinguishing gestational thrombocytopenia from immune thrombocytopenia (ITP), preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), or thrombotic thrombocytopenic purpura (TTP) is essential since the treatment differs widely. Occasionally the management of mother and infant involves the expeditious recognition of neonatal alloimmune thrombocytopenia (NAIT), a condition that is responsible for severe life-threatening bleeding of the newborn. Additionally, inherited and acquired bleeding disorders affect pregnant women disproportionately and often require careful monitoring of coagulation parameters to prevent bleeding in the puerperium. Finally, venous thromboembolism (VTE) during pregnancy is still largely responsible for mortality during pregnancy, and the diagnosis, treatment options and guidelines for prevention of VTE during pregnancy are explored. Published by Elsevier Inc.

Cotrimoxazole Prophylaxis and Risk of Severe Anemia or Severe Neutropenia in HAART-Exposed, HIV-Uninfected Infants

PubMed Central

Dryden-Peterson, Scott; Jayeoba, Oluwemimo; Hughes, Michael D.; Jibril, Haruna; McIntosh, Kenneth; Modise, Taolo A.; Asmelash, Aida; Powis, Kathleen M.; Essex, Max; Shapiro, Roger L.; Lockman, Shahin

2013-01-01

Background Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia. Methods We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana. Results A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure–risk difference, −0.69% (95% confidence interval [CI] −2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI −1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93). Conclusions Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1–6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants. ClinicalTrials.gov Registration Numbers NCT01086878 (http://clinicaltrials.gov/show/NCT01086878), NCT00197587 (http://clinicaltrials.gov/show/NCT00197587), and NCT00270296 (http://clinicaltrials.gov/show/NCT00270296). PMID:24086319

Thiotepa 10 mg/kg Treatment Regimen Is Superior to Thiotepa 5 mg/kg in TBF Conditioning in Patients Undergoing Allogeneic Stem-Cell Transplantation.

PubMed

El-Cheikh, Jean; Massoud, Radwan; Moukalled, Nour; Haffar, Basel; Assi, Hazem; Zahreddine, Ammar; Mahfouz, Rami; Bazarbachi, Ali

2018-05-01

The optimal intensity of myeloablation with a reduced-toxicity conditioning regimen to decrease relapse rate after allogeneic stem-cell transplantation without increasing transplant-related mortality (TRM) has not been well established. We compared outcomes between 5 mg/kg (T5) and 10 mg/kg (T10) thiotepa-based conditioning regimens in 29 adults who underwent allogeneic stem-cell transplantation for hematologic malignancies. After a median follow-up of 11 months, TRM was 0% and 14% at 100 days and 1 year, respectively, with TRM observed only in the T5 group (P = .016). The relapse incidence at 1 year was 20%. No patient had disease in first complete remission at the time of transplantation. At 1 year, progression-free and overall survival were 30% versus 87% (P = .012) and 46% versus 87% (P = .008) in the T5 and T10 groups, respectively. In univariate and multivariate analysis, only age at transplantation and total dose of thiotepa had a significant impact on TRM, overall, and progression-free survival. Patients deemed fit to receive T10-based conditioning for allogeneic stem-cell transplantation to treat high-risk hematologic malignancies had better overall and progression-free survival than those who received T5 with no additional toxicities. Patients should be stratified before conditioning, and those judged fit should receive T10, while the others should consider alternative reduced-intensity conditioning regimens. Copyright © 2018 Elsevier Inc. All rights reserved.

Pentostatin and Rituximab Therapy for Previously Untreated B-CLL

PubMed Central

Kay, Neil E.; Wu, Wenting; Kabat, Brian; LaPlant, Betsy; Lin, Thomas S.; Byrd, John C.; Jelinek, Diane F.; Grever, Michael R.; Zent, Clive S.; Call, Timothy G.; Shanafelt, Tait D.

2010-01-01

We have shown that the combination of pentostatin (P), cyclophosphamide (C) and rituximab (R) achieves an overall response (OR) rate >90% with more than 40% complete responses (CR) in patients with untreated CLL. To evaluate if the tolerability of this regimen could be enhanced without sacrificing efficacy, we conducted a phase II trial of P and R without cyclophosphamide, using a higher P dose (4 mg/m2). Among the 33 patients enrolled, 82% were male, median age was 65 (9 patients ≥70 years) and 64% were Rai stage III-IV. The OR rate was 76% with 9 CR (27%), 5 nPR, and 11 PRs. At the time of this analysis, 29/33 patients are still alive and the median follow up for patients still alive is 14 months (range: 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity and 5 (15%) experienced grade 3 or higher non-hematologic toxicity. Comparison of this trial to our previous PCR trial showed that patients treated with PCR had a higher OR rate (91% vs. 76%) and CR rate (41% vs. 27%) compared to patients treated with PR. Median treatment-free survival for all accrued patients was notably longer in PCR treated patients compared to PR (30 vs. 16 months). These findings suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for treatment of CLL. PMID:20187101

Impact of Chemotherapy on Normal Tissue Complication Probability Models of Acute Hematologic Toxicity in Patients Receiving Pelvic Intensity Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazan, Jose G.; Luxton, Gary; Kozak, Margaret M.

Purpose: To determine how chemotherapy agents affect radiation dose parameters that correlate with acute hematologic toxicity (HT) in patients treated with pelvic intensity modulated radiation therapy (P-IMRT) and concurrent chemotherapy. Methods and Materials: We assessed HT in 141 patients who received P-IMRT for anal, gynecologic, rectal, or prostate cancers, 95 of whom received concurrent chemotherapy. Patients were separated into 4 groups: mitomycin (MMC) + 5-fluorouracil (5FU, 37 of 141), platinum ± 5FU (Cis, 32 of 141), 5FU (26 of 141), and P-IMRT alone (46 of 141). The pelvic bone was contoured as a surrogate for pelvic bone marrow (PBM) andmore » divided into subsites: ilium, lower pelvis, and lumbosacral spine (LSS). The volumes of each region receiving 5-40 Gy were calculated. The endpoint for HT was grade ≥3 (HT3+) leukopenia, neutropenia or thrombocytopenia. Normal tissue complication probability was calculated using the Lyman-Kutcher-Burman model. Logistic regression was used to analyze association between HT3+ and dosimetric parameters. Results: Twenty-six patients experienced HT3+: 10 of 37 (27%) MMC, 14 of 32 (44%) Cis, 2 of 26 (8%) 5FU, and 0 of 46 P-IMRT. PBM dosimetric parameters were correlated with HT3+ in the MMC group but not in the Cis group. LSS dosimetric parameters were well correlated with HT3+ in both the MMC and Cis groups. Constrained optimization (0« less

Analyzing temozolomide medication errors: potentially fatal.

PubMed

Letarte, Nathalie; Gabay, Michael P; Bressler, Linda R; Long, Katie E; Stachnik, Joan M; Villano, J Lee

2014-10-01

The EORTC-NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47% of errors, followed by dispensing errors, which accounted for 13 or 29%. Seven reports or 16% were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13%), to hospitalization for other adverse events (13%) or death (18%). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

PubMed

Latagliata, Roberto; Montagna, Chiara; Porrini, Raffaele; Di Veroli, Ambra; Leonetti, Sabrina Crescenzi; Niscola, Pasquale; Ciccone, Fabrizio; Spadea, Antonio; Breccia, Massimo; Maurillo, Luca; Rago, Angela; Spirito, Francesca; Cedrone, Michele; De Muro, Marianna; Montanaro, Marco; Andriani, Alessandro; Bagnato, Antonino; Montefusco, Enrico; Alimena, Giuliana

2016-06-01

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Milestones of Hematopoietic Stem Cell Transplantation – From First Human Studies to Current Developments

PubMed Central

Juric, Mateja Kralj; Ghimire, Sakhila; Ogonek, Justyna; Weissinger, Eva M.; Holler, Ernst; van Rood, Jon J.; Oudshoorn, Machteld; Dickinson, Anne; Greinix, Hildegard T.

2016-01-01

Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA) system allowed improved donor selection, including HLA-identical related and unrelated donors. Besides bone marrow, other stem cell sources like granulocyte-colony stimulating-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from GvL or antitumor effects. Whereas in the early years, malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal; nowadays, allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity. This chapter will summarize the key milestones of HSCT and introduce current developments. PMID:27881982

Aspirin Is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction.

PubMed

Feher, Attila; Kampaktsis, Polydoros N; Parameswaran, Rekha; Stein, Eytan M; Steingart, Richard; Gupta, Dipti

2017-02-01

Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI). Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005-2014 were reviewed. sTP was defined as a platelet count <50,000 cells per µL within 7 days of AMI. Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p  = .0001) and thienopyridine treatment (27% vs. 3%; p  = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p  = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p  = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use. Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding. The Oncologist 2017;22:213-221 Implications for Practice: In patients with hematologic malignancies and acute myocardial infarction with severe thrombocytopenia (platelet count < 50,000 cells/µL), guideline-recommended medical therapy is often withheld because of the fear of major bleeding. In this study, aspirin therapy was associated with improved survival without an increase in major bleeding in this high-risk patient cohort. © AlphaMed Press 2017.

Toxicological evaluation of hydroethanolic extract of Helicteres sacarolha A. St.- Hil. et al.

PubMed

Balogun, Sikiru Olaitan; da Silva, Iberê Ferreira; Colodel, Edson Moleta; de Oliveira, Ruberlei Godinho; Ascêncio, Sérgio Donizeti; Martins, Domingos Tabajara de Oliveira

2014-11-18

Helicteres sacarolha, popularly known in Brazil as 'rosquinha', 'sacarolhas', 'semente-de-macaco', is widely distributed in different phytogeographic zones in Brazil. Preparations from its roots and leaves are employed in popular Brazilian medicine in the treatments of ailments such as peptic ulcer, hypertension among others. Cytotoxicity, acute oral and subchronic toxicity of the hydroethanolic extract of Helicteres sacrolha was investigated as well as the classes of phytochemical present in the extract. Hydroethanolic (70%) extract of Helicteres sacarolha (HEHs) was prepared by maceration. Potential cytotoxicity was evaluated in CHO-k1 cells. Acute administration of HEHs was done in mice as a single dose up to 5000mg/kg and subchronic oral toxicity study for 30 days in Wistar rats at daily oral doses of 0, 250 and 750mg/kg b.w. Clinical observations and toxicological related parameters were determined every 6 days. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Selected secondary metabolites detected were quantified by UV-spectrophotometry and high performance liquid chromatography (HPLC). The extract was non-cytotoxic to CHO-k1 cells. In acute oral toxicity, there was no mortality or clinical alterations in the female mice, at all doses, except for the transient diarrhea observed at 5000mg/kg acute. Doses up to 2000mg/kg caused no mortality or treatment-related clinical manifestations in the male mice, but treatment-related alterations were however observed at 4000mg/kg, with mortalities recorded at 5000mg/kg. During the subchronic oral toxicity study, no mortality or treatment-related clinical signs were observed. Differences in relative organ weight, hematological parameters and histopathology observations between the treated and the control groups were considered not to be treatment-related. Spectrophotometric analysis revealed the presence of relatively high content of phenolics and flavonoids in HEHs. HPLC analysis confirmed the presence of the quantified compounds and demonstrated the presence of ellagic acid, morin and naringin. Our results confirmed that HEHs have a broad safety margin for therapeutic use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Setup Variations in Radiotherapy of Anal Cancer: Advantages of Target Volume Reduction Using Image-Guided Radiation Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Yijen, E-mail: yichen@coh.org; Suh, Steve; Nelson, Rebecca A.

2012-09-01

Purpose: To define setup variations in the radiation treatment (RT) of anal cancer and to report the advantages of image-guided RT (IGRT) in terms of reduction of target volume and treatment-related side effects. Methods and Materials: Twelve consecutive patients with anal cancer treated by combined chemoradiation by use of helical tomotherapy from March 2007 to November 2008 were selected. With patients immobilized and positioned in place, megavoltage computed tomography (MVCT) scans were performed before each treatment and were automatically registered to planning CT scans. Patients were shifted per the registration data and treated. A total of 365 MVCT scans weremore » analyzed. The primary site received a median dose of 55 Gy. To evaluate the potential dosimetric advantage(s) of IGRT, cases were replanned according to Radiation Therapy Oncology Group 0529, with and without adding recommended setup variations from the current study. Results: Significant setup variations were observed throughout the course of RT. The standard deviations for systematic setup correction in the anterior-posterior (AP), lateral, and superior-inferior (SI) directions and roll rotation were 1.1, 3.6, and 3.2 mm, and 0.3 Degree-Sign , respectively. The average random setup variations were 3.8, 5.5, and 2.9 mm, and 0.5 Degree-Sign , respectively. Without daily IGRT, margins of 4.9, 11.1, and 8.5 mm in the AP, lateral, and SI directions would have been needed to ensure that the planning target volume (PTV) received {>=}95% of the prescribed dose. Conversely, daily IGRT required no extra margins on PTV and resulted in a significant reduction of V15 and V45 of intestine and V10 of pelvic bone marrow. Favorable toxicities were observed, except for acute hematologic toxicity. Conclusions: Daily MVCT scans before each treatment can effectively detect setup variations and thereby reduce PTV margins in the treatment of anal cancer. The use of concurrent chemotherapy and IGRT provided favorable toxicities, except for acute hematologic toxicity.« less

Acute and sub-chronic oral toxicity assessment of the aqueous extract leaves of Ficus glumosa Del. (Moraceae) in rodents.

PubMed

Ntchapda, Fidèle; Abakar, Djedouboum; Kom, Blaise; Nana, Paulin; Hamadjida, Adjia; Dimo, Théophile

2014-01-01

Ficus glumosa Del (Moraceae), a plant used in traditional medicine in Cameroon, Senegal, and East Africa for the treatment of edema, hemorrhoid, cardiovascular diseases especially hypertension. The present study evaluated the potential toxicity of the aqueous extract of the leaves of F.glumosa in acute and sub-chronic administration in rodents. Acute toxicity was evaluated on 3 months old mice of both sexes and weighing 20-30 g. A single dose (2-12 g/kg) of F. glumosa was administered orally to mice. Animal behavior, adverse effects, and mortality were determined for 14 days. In sub-chronic toxicity studied in both sexes of 9 weeks old rats and weighing 100-120 g at the start of the experiment, animals were treated orally with a daily dose of 300, 600 and 1200 mg/kg of the aqueous extract of the leaves of F. glumosa for 6 weeks. The body weight change, food, and water consumption, were determined throughout the experimental period, while the relative organ weights, the hematological and biochemical parameters of blood and urine, as well as the histology of tissues kidney and liver, were recorded at the end of the experiment. For acute treatment, no dose used induced critical behavioral changes or death. In sub-chronic treatment, daily oral administration of F. glumosa at the dose of 300, 600, and 1200 mg/kg resulted in a significant increase in body weight relative to food and water consumption in the last week of treatment. The relative organ weights were not affected by treatment. No hematological changes were observed except the significant increase in platelets. Aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total protein, increased while the total cholesterol, triacylglycerol, conjugated bilirubin, and total bilirubin significantly decreased. Index of renal function showed a decrease of creatinine, urea, uric acid and Na(+), Cl(-) and Ca(2+), and inorganic phosphate. The histology of liver and kidney showed no significant alteration of tissue. These observations support the traditional use of F. glumosa in the treatment of hypertension. These results have shown that F. glumosa has a safety margin for therapeutic use.

Exposure to sub-acute doses of fipronil and buprofezin in combination or alone induces biochemical, hematological, histopathological and genotoxic damage in common carp (Cyprinus carpio L.).

PubMed

Qureshi, Irfan Zia; Bibi, Asia; Shahid, Sana; Ghazanfar, Madiha

2016-10-01

Use of pesticides or insecticides can be highly toxic to aquatic life forms due to leaching and agricultural runoff, rains or flood. Fipronil (FP) is a GABA receptor inhibitor, while buprofezin (BPFN) is an insect growth regulator. Presently, we exposed groups of aquaria acclimated carp fish (Cyprinus carpio) for 96h to sub-lethal concentrations of fipronil (400μgL(-1); 9.15×10(-7)molL(-1)) and buprofezin (BPFN, 100mgL(-1); 1.072×10(-6)molL(-1)) singly or in combination. The extent of damage was assessed at biochemical, hematological, molecular biological and histopathological level. Results obtained in treated fish were compared statistically with those of control non-treated fish and also among treatment groups. Significance level was p<0.05. Compared to control, serum total protein and globulin concentrations decreased significantly (p<0.0001) in fish treated with FP; while albumin concentration remained unaltered with all treatments. Glucose concentration decreased significantly (p<0.002) in fish treated with FP. In contrast, combined FP+BPFN treatment and BPFN treatment caused insignificant elevation of glucose concentration. Hematological assessment demonstrated significant decrease in red blood cell and thrombocyte counts, hemoglobin concentration and hematocrit percent; while white blood cell count showed an increase in all treatment groups (p<0.0001). Blood smears from pesticide treated fish revealed aberrant erythrocyte morphologies which included necrosis, micronuclear formation and hyperchromatosis. DNA laddering assay carried out on whole blood demonstrated excessive smear formation in combined FP+BPFN and BPFN treatment groups but no smear formation was noticeable in FP treated fish. Compared to control, whole blood DNA content increased significantly in the combined FP+BPFN and BPFN treatment groups (p<0.001 and p<0.009). With all treatments histopathological changes observed in the gills were: epithelial uplifting and necrosis of lamellae, lamellar atrophy, disruption of cartilaginous core, fusion and disorganization of lamellae and telangiectasia. In liver these were: karyorrhexis, hepatocellular hypertrophy, nuclear hypertrophy, melanomacrophage aggregates and central vein contraction, while in the kidney: deterioration of glomerulus and dilatation of Bowman's space, dilatation of renal tubules, thyroidisation, altered tubular lumen, nuclear hypertrophy, cellular atrophy, and cellular necrosis were the outcome. Our study revealed that FP and BPFN produce highly toxic effects on fish when given in combination or singly. To our knowledge, this is the first report on toxicity caused by FP and BPFN in single and combined state. Copyright © 2016 Elsevier B.V. All rights reserved.

Pretreatment Hematologic Findings as Novel Predictive Markers for Facial Palsy Prognosis.

PubMed

Wasano, Koichiro; Kawasaki, Taiji; Yamamoto, Sayuri; Tomisato, Shuta; Shinden, Seiichi; Ishikawa, Toru; Minami, Shujiro; Wakabayashi, Takeshi; Ogawa, Kaoru

2016-10-01

To examine the relationship between prognosis of 2 different facial palsies and pretreatment hematologic laboratory values. Multicenter case series with chart review. Three tertiary care hospitals. We examined the clinical records of 468 facial palsy patients who were treated with an antiviral drug in combination with either oral or intravenous corticosteroids in participating hospitals between 2010 and 2014. Patients were divided into a Bell's palsy group or a Hunt's palsy group. We used the Yanagihara facial nerve grading system to grade the severity of facial palsy. "Recovery" from facial palsy was defined as achieving a Yanagihara score ≥36 points within 6 months of onset and having no accompanying facial contracture or synkinesis. We collected information about pretreatment hematologic findings, demographic data, and electrophysiologic test results of the Bell and Hunt group patients who recovered and those who did not. We then compared these data across the 2 palsy groups. In the Bell's palsy group, recovered and unrecovered patients differed significantly in age, sex, electroneuronography score, stapedial muscle reflex, neutrophil rate, lymphocyte rate, neutrophil-to-lymphocyte ratio, and initial Yanagihara score. In the Hunt's palsy group, recovered and unrecovered patients differed in age, electroneuronography score, stapedial muscle reflex, monocyte rate, platelet count, mean corpuscular volume, and initial Yanagihara score. Pretreatment hematologic findings, which reflect the severity of inflammation and bone marrow dysfunction caused by a virus infection, are useful for predicting the prognosis of facial palsy. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Anemia and Red Blood Cell Abnormalities in HIV-Infected and HIV-Exposed Breastfed Infants: A Secondary Analysis of the Kisumu Breastfeeding Study.

PubMed

Odhiambo, Collins; Zeh, Clement; Ondoa, Pascale; Omolo, Paul; Akoth, Benta; Lwamba, Humphrey; Lando, Richard; Williamson, John; Otieno, Juliana; Masaba, Rose; Weidle, Paul; Thomas, Timothy

2015-01-01

Anemia results in increased morbidity and mortality, underscoring the need to better understand its pathophysiology amongst HIV-exposed and infected children in sub-Saharan Africa, the region where most infant HIV exposure and infections occur. This analysis used samples obtained from children in the Kisumu Breastfeeding Study (KiBS). KiBS was a longitudinal phase IIB, open-label, one-arm clinical trial, designed to investigate the safety, tolerability and effectiveness of a maternal triple-antiretroviral (ARV) regimen for prevention of mother-to-child transmission (PMTCT) of HIV, during late pregnancy and early infancy while breastfeeding. Blood samples from 482 children were obtained at birth, 2, 6, 10 and 14 weeks and 6, 9, 12, 18 and 24 months. Severity of anemia was graded using the NIH Division of AIDS (DAIDS) toxicity tables. We describe the proportion of children with anemia and anomalies in red blood cell parameters at various time points over 24 months and compare rates of anemia between HIV-infected and HIV-uninfected children and by mothers' ARV regimen and infant malaria infection. The proportion of children with anemia significantly increased after the breastfeeding period in both HIV-infected and HIV-uninfected children with higher proportion among HIV-infected children compared to HIV-uninfected children (RR: 1.72; CI: 1.22-2.44, p = 0.002). Maternal triple-antiretroviral regimen was not associated with infant anemia (p = 0.11). There was no significant difference in mean hemoglobin between HIV-uninfected children with and without malaria at each time point except at 24 months. A relatively lower proportion of children with severe anemia during the breastfeeding period suggest that exposure to mother's triple antiretroviral combinations through breast milk, posed minimal risk of hematologic toxicity.

Toxicological safety assessment of genetically modified Bacillus thuringiensis with additional N-acyl homoserine lactonase gene.

PubMed

Peng, Donghai; Zhou, Chenfei; Chen, Shouwen; Ruan, Lifang; Yu, Ziniu; Sun, Ming

2008-01-01

The aim of the present study is to evaluate the toxicology safety to mammals of a genetically modified (GM) Bacillus thuringiensis with an additional N-acyl homoserine lactones gene (aiiA), which possesses insecticidal activity together with restraint of bacterial pathogenicity and is intended for use as a multifunctional biopesticide. Safety assessments included an acute oral toxicity test and 28-d animal feeding study in Wistar rats, primary eye and dermal irritation in Zealand White rabbits, and delayed contact hypersensitivity in guinea pigs. Tests were conducted using spray-dried powder preparation. This GM product showed toxicity neither in oral acute toxicity test nor in 28-d animal feeding test at a dose of 5,000 mg/kg body weight. During the animal feeding test, there were no significant differences in growth, food and water consumption, hematology, blood biochemical indices, organ weights, and histopathology finding between rats in controls and tested groups. Tested animals in primary eye and dermal irritation and delayed contact hypersensitivity test were also devoid of any toxicity compared to controls. All the above results demonstrated that the GM based multifunctional B. thuringiensis has low toxicity and low eye and dermal irritation and would not cause hypersensitivity to laboratory mammals and therefore could be regarded as safe for use as a pesticide.

Acute and Subchronic Toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from Chloroform Bay Leaf Extract (Eugenia Polyantha W.) with Palm Kernel Oil as A Carrier

NASA Astrophysics Data System (ADS)

Prihapsara, F.; Mufidah; Artanti, A. N.; Harini, M.

2018-03-01

The present study was aimed to study the acute and subchronic toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with Palm Kernel Oil as carrier. In acute toxicity test, five groups of rat (n=5/groups) were orally treated with Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with doses at 48, 240, 1200 and 6000 mg/kg/day respectively, then the median lethal dose LD50, advers effect and mortality were recorded up to 14 days. Meanwhile, in subchronic toxicity study, 4 groups of rats (n=6/group) received by orally treatment of SNEDDS from chloroform bay leaf extract with doses at 91.75; 183.5; 367 mg/kg/day respectively for 28 days, and biochemical, hematological and histopatological change in tissue such as liver, kidney, and pancreatic were determined. The result show that LD50 is 1045.44 mg/kg. Although histopathological examination of most of the organs exhibited no structural changes, some moderate damage was observed in high‑ dose group animals (367 mg/kg/day). The high dose of SNEDDS extract has shown mild signs of toxicity on organ function test.

Nonclinical Safety Assessment of Morus alba L. Fruits: Study of 90-D Toxicity in Sprague Dawley Rats and Genotoxicity in Salmonella.

PubMed

Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

2016-05-01

Morus alba L. is a traditional herb with a long history of consumption, both as an edible fruit and as medicine. However, its safety evaluation has not yet been established. The objective of this study was to evaluate subchronic oral toxicity and genotoxicity of M. alba L. fruits (MFE). The subchronic toxicity after daily oral administration of MFE at 0, 40, 200, and 1000 mg/kg for 90 d was examined in Sprague Dawley (SD) rats. MFE administration did not lead to death, adverse effects, change in food and water consumption, and body weight gain. Significant toxic effects were not found within the parameters of organ weight, biochemical values, and hematological and urine analysis between the control and the MFE group. The genotoxicity of MFE was assayed by Ames test in Salmonella typhimurium strains TA98, TA102, and TA1535. No genotoxicity was found in all the tested strains. Thus in this study, a no-observed-adverse-effect level for MFE in 90 d repeated oral toxicity study in rats was determined to be greater than 1000 mg/kg regardless of gender. The results also suggested that MFE does not have a genotoxicity potential. © 2016 Institute of Food Technologists®

Marked Hypofibrinogenemia and Gastrointestinal Bleeding After Copperhead (Agkistrodon contortrix) Envenomation.

PubMed

Kopec, Kathryn T; Yen, May; Bitner, Matthew; Evans, C Scott; Gerardo, Charles J

2015-12-01

Compared with other crotaline envenomations, copperhead envenomations have historically been reported as having less severe hematologic venom effects and rarely hemorrhage. We report a case of clinically significant gastrointestinal bleeding after a copperhead (Agkistrodon contortrix) envenomation. A 52-year-old woman with a history of systemic lupus erythematosus was bitten on her right medial ankle after which hypofibrinogenemia and hematochezia developed. The symptoms resolved after repeated administration of Crotalidae polyvalent immune Fab (ovine) antivenom. She was discharged without further complications 2 days later. Although copperhead envenomations are classically considered less severe than other crotaline envenomations, this case demonstrates the potential of the venom to produce clinically significant hematologic effects. Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Prolonged thrombocytopenia in a child with severe neonatal alloimmune reaction and Noonan syndrome.

PubMed

Salva, Inês; Batalha, Sara; Maia, Raquel; Kjollerstrom, Paula

2016-06-01

Fetomaternal alloimmune thrombocytopenia (FMAIT) caused by maternal antibodies is the leading cause of severe neonatal thrombocytopenia. A 1-month-old Caucasian girl was referred to our Hematology Clinic for persistent thrombocytopenia diagnosed after a bleeding episode. Diagnostic tests suggested FMAIT. Mild thrombocytopenia persisted for 18 months, and subsequent findings of dysmorphic facies, short stature and mild pulmonary stenosis led to the hypothesis of Noonan syndrome (NS), which was confirmed by genetic test. Other hematological abnormalities were excluded and she had no further bleeding episodes. This case illustrates the possibility of different diagnoses with the same clinical manifestations. The persistence of thrombocytopenia longer than expected associated with typical physical features led to the diagnosis of NS.

Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study.

PubMed

Houillier, Caroline; Ghesquières, Hervé; Chabrot, Cécile; Soussain, Carole; Ahle, Guido; Choquet, Sylvain; Nicolas-Virelizier, Emmanuelle; Bay, Jacques-Olivier; Vargaftig, Jacques; Gaultier, Claude; Touitou, Valérie; Martin-Duverneuil, Nadine; Cassoux, Nathalie; Le Garff-Tavernier, Magali; Costopoulos, Myrto; Faurie, Pierre; Hoang-Xuan, Khê

2017-06-01

Primary CNS lymphoma (PCNSL) is chemosensitive to high-dose methotrexate-based chemotherapy. However, responses in the elderly are short-lasting and outcome is poor. Given that radiotherapy and intensive chemotherapy expose elderly to severe toxicities, alternative consolidation approaches need to be evaluated. In this multicenter study, we retrospectively analyzed consecutive patients with newly-diagnosed PCNSL, aged >60, treated with a (R)-MPV-AAA regimen. The regimen consisted of three 28-day cycles of methotrexate (3.5 g/m 2 D1, D15), procarbazine, vincristine, followed by three 28-day cycles of cytarabine consolidation (3 g/m 2 D1-2). Addition of rituximab (375 mg/m 2 D1) was optional. The results were compared with the historical MPV-A regimen. Ninety patients received the (R)-MPV-AAA regimen with (n = 39) or without (n = 51) rituximab. Median age was 68 and median KPS 60. 55% of patients achieved a complete response, 8% a partial response and 37% progressed. The median PFS was 10 months, the median OS 28.1 months. Toxicity was mainly hematological, with 54 and 51% of grade III-IV neutropenia and thrombopenia. The response rate was higher in patients receiving rituximab (77 vs. 53%; p = 0.03), whereas no difference was observed in terms of PFS or OS. When comparing the results to the historical MPV-A, there was no difference in terms of response rate, PFS or OS, but a higher rate of hematotoxicity. This study suggests that extending cytarabine consolidation after methotrexate-based chemotherapy does not improve the MPV-A efficacy but increases toxicity in the elderly. The addition of rituximab may improve the response rate, but its impact on final outcome remains unclear.

Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

PubMed

Sun, Xin; Sun, Li; Zhang, Shu-Ling; Xiong, Zhi-Cheng; Ma, Jie-Tao; Han, Cheng-Bo

2017-01-01

S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.

Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ(+) thalassemia with IVS1-5(G→C) mutation.

PubMed

Dehury, Snehadhini; Purohit, Prasanta; Patel, Siris; Meher, Satyabrata; Kullu, Bipin Kishore; Sahoo, Lulup Kumar; Patel, Nayan Kumar; Mohapatra, Alok Kumar; Das, Kishalaya; Patel, Dilip Kumar

2015-06-01

Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. We registered 318 patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with ≥2 years of hydroxyurea treatment were studied. The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P < 0.0001). %HbF level, hemoglobin, MCV and MCH increased significantly, whereas HbS, WBC, platelet count, serum-bilirubin and LDH levels decreased significantly after HU therapy. It has been observed that along with fairly subtle hematological changes following HU therapy, there was a substantial clinical improvement occurred in these patients. Transient myelotoxicity was observed in 4.8%. There was minimal gonadal toxicity without affecting reproductive function. In view of easy affordability, better acceptability, minimal toxicity, the need of infrequent monitoring and its potential effectiveness, low and fixed dose of hydroxyurea is suitable for treatment of patients with HbSβ(+) -thalassemia in resource poor setting. © 2014 Wiley Periodicals, Inc.

More severe toxicity of genetic polymorphisms on MTHFR activity in osteosarcoma patients treated with high-dose methotrexate

PubMed Central

Xie, Lu; Guo, Wei; Yang, Yi; Ji, Tao; Xu, Jie

2018-01-01

5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = −0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival. PMID:29545912

Cobalt toxicity in humans-A review of the potential sources and systemic health effects.

PubMed

Leyssens, Laura; Vinck, Bart; Van Der Straeten, Catherine; Wuyts, Floris; Maes, Leen

2017-07-15

Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B 12 , excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300μg/l (100μg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co 2+ . As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co 2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies. Copyright © 2017 Elsevier B.V. All rights reserved.

Mechanisms of lead-induced poisoning.

PubMed

Nemsadze, K; Sanikidze, T; Ratiani, L; Gabunia, L; Sharashenidze, T

2009-01-01

Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic circulatory, neurological, hematological, gastrointestinal, reproductive and immunological pathologies. The mechanism of lead induced toxicity is not fully understood. The prime targets to lead toxicity are the heme synthesis enzymes, thiol-containing antioxidants and enzymes (superoxide dismutase, catalase, glutathione peroxidase, glucose 6-phosphate dehydrogenase and antioxidant molecules like GSH). The low blood lead levels are sufficient to inhibit the activity of these enzymes and induce generation of reactive oxygen species and intensification oxidative stress. Oxidative stress plays important role in pathogenesis of lead-induced toxicity and pathogenesis of coupled disease. The primary target of lead toxicity is the central nervous system. There are different cellular, intracellular and molecular mechanisms of lead neurotoxicity: such as induction of oxidative stress, intensification of apoptosis of neurocites, interfering with Ca(2+) dependent enzyme like nitric oxide synthase. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension and cardiovascular disease. The vascular endothelium is now regarded as the main target organ for the toxic effect of lead. Lead affects the vasoactive function of endothelium through the increased production of reactive oxygen species, inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species, leading to a limiting nitric oxide availability, impairing nitric oxide signaling. This review summarizes recent findings of the mechanism of the lead-induced toxicity and possibilities of its prevention.

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Reid, Joel M; Sloan, Jeff A; Ames, Matthew M; Adjei, Alex A; Rubin, Joseph; Bagniewski, Pamela G; Atherton, Pamela; Rayson, Daniel; Goldberg, Richard M; Erlichman, Charles

2002-03-01

To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being

Red blood cell transfusion in the resuscitation of septic patients with hematological malignancies.

PubMed

Mirouse, Adrien; Resche-Rigon, Matthieu; Lemiale, Virginie; Mokart, Djamel; Kouatchet, Achille; Mayaux, Julien; Vincent, François; Nyunga, Martine; Bruneel, Fabrice; Rabbat, Antoine; Lebert, Christine; Perez, Pierre; Renault, Anne; Meert, Anne-Pascale; Benoit, Dominique; Hamidfar, Rebecca; Jourdain, Mercé; Darmon, Michaël; Azoulay, Elie; Pène, Frédéric

2017-12-01

Indications for red blood cell (RBC) transfusion in septic acute circulatory failure remain unclear. We addressed the practices and the prognostic impact of RBC transfusion in the early resuscitation of severe sepsis and septic shock in patients with hematological malignancies. We performed a retrospective analysis of a prospectively collected database of patients with hematological malignancies who required intensive care unit (ICU) admission in 2010-2011. Patients with a main admission diagnosis of severe sepsis or septic shock were included in the present study. We assessed RBC transfusion during the first two days as part of initial resuscitation. Among the 1011 patients of the primary cohort, 631 (62.4%) were admitted to the ICU for severe sepsis (55%) or septic shock (45%). Among them, 210 (33.3%) patients received a median of 2 [interquartile 1-3] packed red cells during the first 48 h. Hemoglobin levels were lower in transfused patients at days 1 and 2 and became similar to those of non-transfused patients at day 3. Early RBC transfusion was more likely in patients with myeloid neoplasms and neutropenia. Transfused patients displayed more severe presentations as assessed by higher admission SOFA scores and blood lactate levels and the further requirements for organ failure supports. RBC transfusion within the first two days was associated with higher day 7 (20.5 vs. 13.3%, p = 0.02), in-ICU (39 vs. 25.2%, p < 0.001) and in-hospital (51 vs. 36.6%, p < 0.001) mortality rates. RBC transfusion remained independently associated with increased in-hospital mortality in multivariate logistic regression (OR 1.52 [1.03-2.26], p = 0.03) and propensity score-adjusted (OR 1.64 [1.05-2.57], p = 0.03) analysis. RBC transfusion is commonly used in the early resuscitation of septic patients with hematological malignancies. Although it was preferentially provided to the most severe patients, we found it possibly associated with an increased risk of death.

The impact of comorbid disease history on all-cause and cancer-specific mortality in myeloid leukemia and myeloma - a Swedish population-based study.

PubMed

Mohammadi, Mohammad; Cao, Yang; Glimelius, Ingrid; Bottai, Matteo; Eloranta, Sandra; Smedby, Karin E

2015-11-05

Comorbidity increases overall mortality in patients diagnosed with hematological malignancies. The impact of comorbidity on cancer-specific mortality, taking competing risks into account, has not been evaluated. Using the Swedish Cancer Register, we identified patients aged >18 years with a first diagnosis of acute myeloid leukemia (AML, N = 2,550), chronic myeloid leukemia (CML, N = 1,000) or myeloma (N = 4,584) 2002-2009. Comorbid disease history was assessed through in- and out-patient care as defined in the Charlson comorbidity index. Mortality rate ratios (MRR) were estimated through 2012 using Poisson regression. Probabilities of cancer-specific death were computed using flexible parametric survival models. Comorbidity was associated with increased all-cause as well as cancer-specific mortality (cancer-specific MRR: AML = 1.27, 95 % CI: 1.15-1.40; CML = 1.28, 0.96-1.70; myeloma = 1.17, 1.08-1.28) compared with patients without comorbidity. Disorders associated with higher cancer-specific mortality were renal disease (in patients with AML, CML and myeloma), cerebrovascular conditions, dementia, psychiatric disease (AML, myeloma), liver and rheumatic disease (AML), cardiovascular and pulmonary disease (myeloma). The difference in the probability of cancer-specific death, comparing patients with and without comorbidity, was largest among AML patients <70 years, whereas in myeloma the difference did not vary by age among the elderly. The probability of cancer-specific death was generally higher than other-cause death even in older age groups, irrespective of comorbidity. Comorbidities associated with organ failure or cognitive function are associated with poorer prognosis in several hematological malignancies, likely due to lower treatment tolerability. The results highlight the need for a better balance between treatment toxicity and efficacy in comorbid and elderly AML, CML and myeloma patients.

Oral manifestations of hematologic and nutritional diseases.

PubMed

Schlosser, Bethanee J; Pirigyi, Megan; Mirowski, Ginat W

2011-02-01

Oral manifestations of hematologic and nutritional deficiencies can affect the mucous membranes, teeth, periodontal tissues, salivary glands, and perioral skin. This article reviews common oral manifestations of hematologic conditions starting with disorders of the white blood cells including cyclic hematopoiesis (cyclic neutropenia), leukemias, lymphomas, plasma cell dyscrasias, and mast cell disorders; this is followed by a discussion of the impact of red blood cell disorders including anemias and less common red blood cell dyscrasias (sickle cell disease, hemochromatosis, and congenital erythropoietic porphyria) as well as thrombocytopenia. Several nutritional deficiencies exhibit oral manifestations. The authors specifically discuss the impact of water-soluble vitamins (B2, B3, B6, B9, B12, and C), fat-soluble vitamins (A, D, and K) and the eating disorders anorexia nervosa and bulimia nervosa on the oral mucosa. Copyright © 2011 Elsevier Inc. All rights reserved.

Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology).

PubMed

Svahn, Johanna; Bagnasco, Francesca; Cappelli, Enrico; Onofrillo, Daniela; Caruso, Silvia; Corsolini, Fabio; De Rocco, Daniela; Savoia, Anna; Longoni, Daniela; Pillon, Marta; Marra, Nicoletta; Ramenghi, Ugo; Farruggia, Piero; Locasciulli, Anna; Addari, Carmen; Cerri, Carla; Mastrodicasa, Elena; Casazza, Gabriella; Verzegnassi, Federico; Riccardi, Francesca; Haupt, Riccardo; Barone, Angelica; Cesaro, Simone; Cugno, Chiara; Dufour, Carlo

2016-07-01

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles

PubMed Central

Venkatasubbu, Gopinath Devanand; Ramasamy, S; Gaddam, Pramod Reddy; Kumar, J

2015-01-01

Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile. PMID:26491315

Health Risk Assessment of Women in Submarines: Reproductive and Developmental Toxicity Evaluation of Major Submarine Atmosphere Components (CO, CO2, and O2) in Rats (Rattus norvegicus) - Phase 1 (Range Finding Study)

DTIC Science & Technology

2011-06-27

study will incorporate new phlebotomy procedures that will reduce the potential for clotting and hemolysis in the blood . The increase of RDW in the...observed blood clotting or hemolysis (≤ 5% of data), which can frequently result in anomalous hematological and/or serum chemistry values, anomalous...exposure concentrations were identified for both males and females, including: (1) increased red blood cell distribution width (RDW) in rats from the

Targeting epigenetics for the treatment of prostate cancer: recent progress and future directions.

PubMed

Lin, Jianqing; Wang, Chenguang; Kelly, Wm Kevin

2013-06-01

Epigenetic aberrations contribute to prostate cancer carcinogenesis and disease progression. Efforts have been made to target DNA methyltransferase and histone deacetylases (HDACs) in prostate cancer and other solid tumors but have not had the success that was seen in the hematologic malignancies. Oral, less toxic, and more specific agents are being developed in solid tumors including prostate cancer. Combinations of epigenetic agents alone or with a targeted agent such as androgen receptor signaling inhibitors are promising approaches and will be discussed further. Copyright © 2013 Elsevier Inc. All rights reserved.

Acute and subchronic toxicity of naturally weathered Exxon Valdez crude oil in mallards and ferrets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, W.A.; Hancock, G.A.; Ford, W.H.

1995-11-01

The toxic properties of naturally weathered Exxon Valdez crude oil (WEVC) were assessed in a battery of acute and subchronic toxicity tests using mallards, Anas platyrhynchos, and European ferrets, Mustela putorius. Adult mallard acute oral toxicity study results indicated no mortalities or signs o toxicity, i.e., no-observed-adverse-effect level (NOAEL) and median lethal dose (LD50) > 5,000 mg/kg. Acute oral feeding and food avoidance tests with ducklings also indicated no toxicity (NOAEL and LC50 > 50,000 mg/kg diet) with no evidence of food avoidance (FAC50 > 20,000 mg/kg diet). No mortalities or toxic signs were noted in a 14-d feeding studymore » with adult birds at dietary concentrations up to 100,000 mg WEVC/kg diet. Among clinical and physiological end points evaluated, the only significant difference noted was an increase in liver: body weight ratios in the 100,000-mg WEVC/kg diet dose group. No differences in clinical chemistry or hematological parameters were noted, and there were no consistent differences in histological evaluations of organ tissues. Daily oral doses of up to 5,000 mg/kg of WEVC over 5 d resulted in minimal effects on ferrets. Increased serum albumin concentrations were observed in the 5,000-mg/kg dose group females and decreased spleen weights were noted in females of all WEVC treatment groups. No other significant observations were noted.« less

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Evaluation of repeated exposure systemic toxicity test of PVC with new plasticizer on rats via dual parenteral routes

PubMed Central

Hou, Li; Fan, Chunguang; Liu, Chenghu; Qu, Qiujin; Wang, Chunren

2018-01-01

Abstract Systemic toxicity caused by repeated exposure to both polar and nonpolar leachables of di(2-ethylhexyl)-1,2-cyclohexane plasticized polyvinyl chloride (PVC) was evaluated with dual routes of parenteral administration method on rats in the study. Experimental group and control group were designed by researchers. Tail intravenous injection with 0.9% sodium chloride injection extracts and intraperitoneal injection with corn oil extracts were conducted to the experimental rats while tail intravenous injection with 0.9% sodium chloride Injection and intraperitoneal injection with corn oil were conducted to the control rats. After 14 days, blood specimens were collected for clinical pathology (hematology and clinical chemistry) analysis. Selected organs were weighed and a histopathological examination was conducted. As a result, compared with the control animals, there were no toxicity-related changes on the parameters above. The results show that the rats do not show obvious systemic toxicity reaction caused by repeated exposure with dual routes of parenteral administration method on rats after administration with both polar and nonpolar exacts of di(2-ethylhexyl)-1,2-cyclohexane plasticized PVC simultaneously up for 14 days. PMID:29423263

In vivo toxicity assessment of non-cadmium quantum dots in BALB/c mice.

PubMed

Lin, Guimiao; Ouyang, Qingling; Hu, Rui; Ding, Zhangchi; Tian, Jinglin; Yin, Feng; Xu, Gaixia; Chen, Qiang; Wang, Xiaomei; Yong, Ken-Tye

2015-02-01

Along with widespread usage of QDs in electronic and biomedical industries, the likelihood of QDs exposure to the environment and humans is deemed to occur when the QD products are degraded or handled as waste for processing. To date, there are very few toxicological reports available in the literature for non-cadmium QDs in animal models. In this work, we studied the long term in vivo toxicity of InP/ZnS QDs in BALB/c mice. The biodistribution, body weight, hematology, blood biochemistry, and organ histology were determined at a very high dosage (25 mg/kg) of InP/ZnS QDs over 84 days period. Our results manifested that the QDs formulation did not result in observable toxicity in vivo within the evaluation period, thereby suggesting that the InP/ZnS QDs can be utilized as optical probes or nanocarrier for selected in vivo biological applications when an optimized dosage is employed. This study investigated the toxicity of quantum dots in BALB/c mice, and concluded that no organotoxicity was detectable despite of using high concentration of InP/ZnS quantum dots with prolonged exposure of 3 months. Copyright © 2015 Elsevier Inc. All rights reserved.

Single-dose Intramuscular-injection Toxicology Test of Water-soluble Carthami-flos and Cervi cornu parvum Pharmacopuncture in a Rat Model.

PubMed

Park, Sunju; Sun, Seung-Ho

2015-09-01

The aim of the study is to investigate both the single-dose intramuscular injection toxicity and the approximate lethal dose of water-soluble Carthami-flos and Cervi cornu parvum pharmacopuncture (WCFC) in male and female Sprague-Dawley (SD) rats. The study was conducted at Biotoxtech Co. according to the Good Laboratory Practice (GLP) regulation and the toxicity test guidelines of the Ministry of Food and Drug Safety (MFDS) after approval of the Institutional Animal Care and Use Committee. Dosages for the control, high dose, middle dose and low dose groups were 0.5 mL/animal of saline and 0.5, 0.25 and 0.125 mL/animal of WCFC, respectively. WCFC was injected into the muscle of the left femoral region by using a disposable syringe (1 mL, 26 gauge). The general symptoms and mortality were observed 30 minutes, 1, 2, 4, and 6 hours after the first injection and then daily for 14 days after the injection. The body weights of the SD rats were measured on the day of the injection (before injection) and on the third, seventh, and fourteenth days after the injection. Serum biochemical and hematologic tests, necropsy examinations, and histopathologic examinations at the injection site were performed after the observation period. No deaths, abnormal clinical symptoms, or significant weight changes were observed in either male or female SD rats in the control or the test (0.125, 0.25, and 0.5 mL/animal) groups during the observation period. No significant differences in hematology and serum biochemistry and no macroscopic abnormalities at necropsy were found. No abnormal reactions at injection sites were noted on the topical tolerance tests. The results of this single-dose toxicity study show that WCFC is safe, its lethal doses in male and female SD rats being estimated to be higher than 0.5 mL/animal.

From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with early-stage nonsmall cell lung cancer.

PubMed

Jeremić, Branislav; Milicić, Biljana

2008-02-15

The authors' single-institution experience in patients with early-stage (I and II) nonsmall cell lung cancer (NSCLC) who were treated between 1980 and 1998 with either conventionally fractionated (CF) radiation therapy (RT), or hyperfractionated (HFX) RT, or HFX RT with concurrent paclitaxel/carboplatin (HFX RT-Pac/C) was reviewed. Seventy-eight patients received 60 grays (Gy) in 30 daily fractions (CF), 116 patients received 69.6 Gy (1.2 Gy twice daily), and 56 patients received 67.6 Gy (1.3 Gy twice daily) with concurrent, low-dose, daily C (25 mg/m2) and Pac (10 mg/m2). Biologically equivalent doses for the 3 groups were 72 Gy, 78 Gy, and 76 Gy, respectively, for acute effects (alpha/beta = 10 Gy) and 120 Gy, 111 Gy, and 111 Gy, respectively, for late effects (alpha/beta = 2 Gy). For all 250 patients, the overall median survival was 27 months, the cause-specific survival was 27 months, the local progression-free survival was 32 months, and distant metastasis-free survival was not achieved; and the respective 5-year survival rates were 27%, 32%, 45%, and 68%. CF achieved significantly inferior survival than either HFX RT alone or HFX RT-Pac/C (P = .0332 and P = .0013, respectively), and no difference was observed between the 2 HFX RT regimens (P = .1934). Only acute hematologic high-grade toxicity (grade >or=3) was more frequent with HFX RT-Pac/C than with either RT alone, whereas other toxicities were similar between the 3 treatment groups. HFX RT with or without concurrent chemotherapy may be better than CF in patients with early-stage NSCLC. The role of chemotherapy deserves further investigation, because the group that received chemotherapy in the current study had a higher incidence of acute high-grade hematologic toxicity. Cancer 2008. (c) 2008 American Cancer Society.

Weekly irinotecan in patients with metastatic colorectal cancer failing 5-fluorouracil-based chemotherapy: efficacy and prognostic factors.

PubMed

Karaoğlu, Aziz; Yalcin, Suayib; Tekuzman, Gülten; Kars, Ayse; Celik, Ismail; Güler, Nilüfer; Ozişik, Yavuz; Türker, Alev; Barişta, Ibrahim; Güllü, Ibrahim

2003-01-01

We evaluated the efficacy and tolerability of weekly irinotecan as a second-line treatment in patients with colorectal cancer failing 5-fluorouracil-based chemotherapy and searched for predictive and prognostic factors. A total of 36 patients were included. Median age was 53 years (range, 33-72). One treatment cycle consisted of irinotecan, 100 mg/m2 weekly, for 4 weeks followed by a 2-week rest. Gender, age, primary site, number of metastatic sites, histologic subtype, differentiation, pretreatment CEA, CA 19-9 and lactate dehydrogenase levels and marker response to treatment were investigated as predictive factors for response to treatment and as prognostic factors in the overall survival and time to progression of the patients. A total of 120 cycles (median, 3 cycles) was delivered. An overall 14% objective response rate (1 complete and 4 partial responses) was achieved. The median response duration was 4 months (range, 2-7). Another 36% of the patients had stable disease for a median duration of 4 months (range, 2-8). Median time-to-disease progression was 4 months and overall median survival was 12 months (95% confidence interval, 9-15). Pretreatment serum CA 19-9 level and marker response to two courses of treatment were found to be clinically significant in time to progression and overall survival. Younger age (< or = 45 years) was a poor prognostic factor associated with a shorter time to progression. The major toxicity was grade 3-4 diarrhea, which occurred in 28% of the patients, and treatment was discontinued in 3 (8%) patients due to toxicity. Other hematological and non-hematological toxicities were mild and manageable. We concluded that weekly irinotecan at the dose of 100 mg/m2 is an effective and tolerable treatment option, with a 50% disease control rate, for patients with colorectal cancer failing previous 5-fluorouracil-based chemotherapy.

Treatment of ovarian cancer with surgery, short-course chemotherapy and whole abdominal radiation.

PubMed

Buser, K; Bacchi, M; Goldhirsch, A; Greiner, R; Diener, P; Sessa, C; Jungi, W F; Forni, M; Leyvraz, S; Engeler, V

1996-01-01

The primary aim was to induce a high number of pCR in early (FIGO IC, IIB + C) - and advanced (FIGO III-IV) - stage ovarian cancer with a surgery plus 4 cycles of cisplatin and melphalan (PAMP) regimen. The second objective was to prevent relapse with WAR in patients in remission after chemotherapy. 218 eligible patients were treated after staging laparotomy with cisplatin 80 mg/sqm i.v. on day 1 and melphalan 12 mg/sqm i.v. on day 2 q 4 weeks. Response was verified by second-look laparotomy. WAR was carried out with the open field technique on a linear accelerator (daily dose: 1.3 Gy, total dose: 29.9 Gy) in patients with pathological or clinical CR or pathological PR with microscopical residual disease. 146/218 patients (67%, 95% CI: 61%-73%) responded to PAMP: 56 (26%) achieved pCR, 24 (11%), cCR, 56 (26%) pPR and 10 (5%) cPR (c = clinical, p = pathological). Multivariate analyses revealed that in advanced stages (92 cases in remission), the achievement of pCR was the most important factor for longer time to failure (TTF) and survival. Only 51/118 (43%) patients in remission received WAR. Early-stage patients <= 55 years were more likely to have WAR than patients older than 55 years (77% vs. 23%; p = 0.02). Advanced-stage patients with cCR were less likely to be irradiated than patients with pCR or pPR (10% vs. 51%; p = 0.003). Toxicity of PAMP was acceptable with 10% of WHO grade 4 hematologic toxicity. Acute hematological toxicity of WAR caused interruption (33%) or incompleteness (33%) of irradiation in the majority of patients. PAMP is an effective treatment for advanced ovarian cancer with a 67% response rate after 4 cycles. For the majority of patients in remission, WAR as a consolidation treatment was hardly feasible. For these patients new treatment modalities to consolidate remission are needed.

Potential of Proton Therapy to Reduce Acute Hematologic Toxicity in Concurrent Chemoradiation Therapy for Esophageal Cancer.

PubMed

Warren, Samantha; Hurt, Christopher N; Crosby, Thomas; Partridge, Mike; Hawkins, Maria A

2017-11-01

Radiation therapy dose escalation using a simultaneous integrated boost (SIB) is predicted to improve local tumor control in esophageal cancer; however, any increase in acute hematologic toxicity (HT) could limit the predicted improvement in patient outcomes. Proton therapy has been shown to significantly reduce HT in lung cancer patients receiving concurrent chemotherapy. Therefore, we investigated the potential of bone marrow sparing with protons for esophageal tumors. Twenty-one patients with mid-esophageal cancer who had undergone conformal radiation therapy (3D50) were selected. Two surrogates for bone marrow were created by outlining the thoracic bones (bone) and only the body of the thoracic vertebrae (TV) in Eclipse. The percentage of overlap of the TV with the planning treatment volume was recorded for each patient. Additional plans were created retrospectively, including a volumetric modulated arc therapy (VMAT) plan with the same dose as for 3D50; a VMAT SIB plan with a dose prescription of 62.5 Gy to the high-risk subregion within the planning treatment volume; a reoptimized TV-sparing VMAT plan; and a proton therapy plan with the same SIB dose prescription. The bone and TV dose metrics were recorded and compared across all plans and variations with respect to PTV and percentage of overlap for each patient. The 3D50 plans showed the highest bone mean dose and TV percentage of volume receiving ≥30 Gy (V 30Gy ) for each patient. The VMAT plans irradiated a larger bone V 10Gy than did the 3D50 plans. The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V 10Gy and bone mean dose, especially for patients with a larger PTV. The results of the present study have shown that proton therapy can reduced bone marrow toxicity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Treosulfan in the Treatment of Advanced Ovarian Cancer - Results of a German Multicenter Non-interventional Study.

PubMed

Chekerov, Radoslav; Kaltenecker, Gabriele; Reichert, Dietmar; Göhler, Thomas; Klare, Peter; Oskay-Özcelik, Gülten; Sauer, Uwe; Wischnik, Arthur; Vehling-Kaiser, Ursula; Becker, Martin; Hutzschenreuter, Ulrich; Ammon, Andreas; Heidrich-Lorsbach, Elke; Sehouli, Jalid

2015-12-01

Data on routine systemic treatment of patients with ovarian cancer are currently available only to a limited degree. The alkylating agent treosulfan is approved in oral (p.o.) and intravenous (i.v.) form for the treatment of ovarian carcinoma. The present non-interventional study analyzed the clinical use of treosulfan in Germany, evaluating the mode of application, toxicity, and response and survival rate. Two hundred and forty-eight ovarian cancer patients in 57 Centers, who received treosulfan mainly either i.v. (5,000-8,000 mg/m(2) d1, q21d or q28d) or p.o. (400-600 mg/m(2) d1-14 or 21, q28d) for at least one therapy cycle were evaluable and were included in the study. With a median age of 70 years (range=36-92 years), predominantly elderly patients received treosulfan treatment. Most participants presented serous histology (131, 52.8%) and advanced-stage FIGO III (122, 49%) or IV (55, 22%) disease. Median ECOG status was 1 (range=0-2), whereas cardiac co-morbidity was common (31%). Treosulfan was usually administered as second- (26%), third- (21%) or fourth-line (17%) therapy. Two hundred and one patients received i.v. and 47 p.o. The most common reason for dose modifications was due to hematological toxicity (46%). The main reason for a therapy discontinuation was progressive disease (38.5%). Response was observed in 25.8% of participants, disease stabilization in 28.6 % and progress in 45.6%. The median progression-free and overall survival was 196 and 405 days, respectively. In predominantly elderly and heavily pre-treated patients with recurrent ovarian cancer, treosulfan featured a clinical relevant efficacy and well-manageable, mostly hematological, toxicity, which resulted in a positive therapeutic index. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma.

PubMed

Noy, Ariela; Lee, Jeannette Y; Cesarman, Ethel; Ambinder, Richard; Baiocchi, Robert; Reid, Erin; Ratner, Lee; Wagner-Johnston, Nina; Kaplan, Lawrence

2015-07-09

The toxicity of dose-intensive regimens used for Burkitt lymphoma prompted modification of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-positive patients. We added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, capped vincristine, and used combination intrathecal chemotherapy. Antibiotic prophylaxis and growth factor support were required; highly active antiretroviral therapy (HAART) was discretionary. Thirteen AIDS Malignancy Consortium centers enrolled 34 patients from 2007 to 2010. Median age was 42 years (range, 19-55 years), 32 of 34 patients were high risk, 74% had stage III to IV BL and CD4 count of 195 cells per μL (range, 0-721 cells per μL), and 5 patients (15%) had CD4 <100 cells per μL. Twenty-six patients were receiving HAART; viral load was <100 copies per mL in 12 patients. Twenty-seven patients had at least one grade 3 to 5 toxicity, including 20 hematologic, 14 infectious, and 6 metabolic. None had grade 3 to 4 mucositis. Five patients did not complete treatments because of adverse events. Eleven patients died, including 1 treatment-related and 8 disease-related deaths. The 1-year progression-free survival was 69% (95% confidence interval [CI], 51%-82%) and overall survival was 72% (95% CI, 53%-84%); 2-year overall survival was 69% (95% CI, 50%-82%). Modifications of the CODOX-M/IVAC regimen resulted in a grade 3 to 4 toxicity rate of 79%, which was lower than that in the parent regimen (100%), without grade 3 to 4 mucositis. Despite a 68% protocol completion rate, the 1-year survival rate compares favorably with 2 studies that excluded HIV-positive patients. This trial was registered at http://clinicaltrials.gov as #NCT00392834. © 2015 by The American Society of Hematology.

Investigation of the Genetics of Hematologic Diseases

ClinicalTrials.gov

2017-10-17

Bone Marrow Failure Syndromes; Erythrocyte Disorder; Leukocyte Disorder; Hemostasis; Blood Coagulation Disorder; Sickle Cell Disease; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Congenital Thrombocytopenia; Severe Congenital Neutropenia; Fanconi Anemia

Nanopharmacology in translational hematology and oncology

PubMed Central

Tomuleasa, Ciprian; Braicu, Cornelia; Irimie, Alexandra; Craciun, Lucian; Berindan-Neagoe, Ioana

2014-01-01

Nanoparticles have displayed considerable promise for safely delivering therapeutic agents with miscellaneous therapeutic properties. Current progress in nanotechnology has put forward, in the last few years, several therapeutic strategies that could be integrated into clinical use by using constructs for molecular diagnosis, disease detection, cytostatic drug delivery, and nanoscale immunotherapy. In the hope of bringing the concept of nanopharmacology toward a viable and feasible clinical reality in a cancer center, the present report attempts to present the grounds for the use of cell-free nanoscale structures for molecular therapy in experimental hematology and oncology. PMID:25092977

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, ShengFa; Teaching and Research Section of Oncology, Guizhou Medical University, Guiyang; Li, Tao

Purpose: The aim of this prospective multi-institutional phase 2 study was to investigate disease control, survival outcomes, and toxicity after thoracic three-dimensional radiation therapy (3D-RT) with concurrent chemotherapy for newly diagnosed stage IV non-small cell lung cancer (NSCLC). Methods and Materials: Eligible patients were 18 to 80 years of age, had a Karnofsky performance status (KPS) score ≥70%, and newly diagnosed stage IV NSCLC with limited metastatic disease (defined as involving ≤3 organs). Patients received platinum-doublet chemotherapy with concurrent irradiation to the primary tumor. Primary endpoints were overall survival (OS) and acute toxicity. Results: From May 2008 to May 2012, 198more » eligible patients were enrolled from 7 cancer centers. Most patients died with distant metastasis; only 10% died with isolated primary recurrence. Median OS time was 13.0 months (95% confidence interval [CI]: 11.7-14.3); OS rates were 53.5% at 1 year, 15.8% at 2 years, and 9.2% at 3 years. Median progression-free survival (PFS) time was 9.0 months (95% CI: 7.7-10.3); corresponding PFS rates were 30.8%, 8.2%, and 6.1%. The 1-year, 2-year, and 3-year local (primary tumor) control rates were 78.8%, 57.7%, and 55.4%. Multivariate analysis showed that delivery of ≥63 Gy to the primary tumor (P=.014), having a primary tumor volume <134 cm{sup 3} (P=.008), and having a stable or higher KPS score after treatment (P=.01) were independent predictors of better OS. The most common severe (grades 3-4) acute toxicities were hematologic: leukopenia (37.9%), thrombocytopenia (10.1%), and anemia (6.9%). No patients experienced grade 4 or 5 radiation-related toxicity; 2.5% had acute grade 3 pneumonitis, and 6.6% had acute grade 3 radiation esophagitis. Conclusions: Thoracic 3D-RT to the primary tumor with concurrent chemotherapy led to satisfactory survival outcomes with acceptable toxicity. Radiation dose, primary tumor volume, and PFS after treatment all predicted survival in these patients with limited-metastasis NSCLC.« less

Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies.

PubMed

Boyle, John; Craciunescu, Oana; Steffey, Beverly; Cai, Jing; Chino, Junzo

2014-11-01

To evaluate the safety of dose escalated radiotherapy using a simultaneous integrated boost technique in patients with locally advanced gynecological malignancies. Thirty-nine women with locally advanced gynecological malignancies were treated with intensity modulated radiation therapy utilizing a simultaneous integrated boost (SIB) technique for gross disease in the para-aortic and/or pelvic nodal basins, sidewall extension, or residual primary disease. Women were treated to 45Gy in 1.8Gy fractions to elective nodal regions. Gross disease was simultaneously treated to 55Gy in 2.2Gy fractions (n=44 sites). An additional sequential boost of 10Gy in 2Gy fractions was delivered if deemed appropriate (n=29 sites). Acute and late toxicity, local control in the treated volumes (LC), overall survival (OS), and distant metastases (DM) were assessed. All were treated with a SIB to a dose of 55Gy. Twenty-four patients were subsequently treated with a sequential boost to a median dose of 65Gy. Median follow-up was 18months. Rates of acute>grade 2 gastrointestinal (GI), genitourinary (GU), and hematologic (heme) toxicities were 2.5%, 0%, and 30%, respectively. There were no grade 4 acute toxicities. At one year, grade 1-2 late GI toxicities were 24.5%. There were no grade 3 or 4 late GI toxicities. Rates of grade 1-2 late GU toxicities were 12.7%. There were no grade 3 or 4 late GU toxicities. Dose escalated radiotherapy using a SIB results in acceptable rates of acute toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Correlation between hematologic profile and transaminase enzymes with hospitalization duration dengue

NASA Astrophysics Data System (ADS)

Tinambunan, E.; Suryani; Katu, S.; Halim, R.; Mubin, A. H.; Sahyuddin

2018-03-01

Dengue is an infectious disease that can be found from mild to severe andaffected the clinical spectrum of the disease. Various hematologic profiles and transaminase enzymes are thought to reflect the severity of the disease thus affecting the hospitalization duration. For determining the correlation between hematological profile and transaminase enzyme to the hospitalization duration in dengue patients, an observational design study with the cross-sectional approach on dengue subjects was from 2 hospitals in Makassar. Hemoglobin, leukocyte, thrombocyte, AST, ALT, PT, and APTT were examined for hospitalization duration. There were 65 samples (34 men, 31 women) with the length of stay <5 days 34 people and ≥ 5 days 31 people. The result of the analysis showed that there was a low correlation of leukocyte value (p = 0.036) and APTT prolongation (p = 0.023) with hospitalization duration of dengue patients. There was no correlation between the elevated of hematocrit value (p = 0.429), thrombocytopenia (p = 1.000), elevated of AST (p = 0.456) and ALT (p = 0.285) on hospitalization duration. In conclusion, low leukocyte values and APTT prolongation correlate with hospitalization duration but did not correlate significantly with hospitalization duration for elevated hematocrit, thrombocytopenia, elevated AST, and ALT.

An atypical case of late-onset systemic lupus erythematosus with systemic lymphadenopathy and severe autoimmune thrombocytopenia/neutropenia mimicking malignant lymphoma.

PubMed

Tamaki, Keita; Morishima, Satoko; Nakachi, Sawako; Kitamura, Sakiko; Uchibori, Sachie; Tomori, Shouhei; Hanashiro, Taeko; Shimabukuro, Natsuki; Tedokon, Iori; Morichika, Kazuho; Nishi, Yukiko; Tomoyose, Takeaki; Karube, Kennosuke; Fukushima, Takuya; Masuzaki, Hiroaki

2017-04-01

Here, we report a rare case of systemic lupus erythematosus (SLE) with conspicuous manifestation of hematological abnormalities. At onset, the 52-year-old male patient showed systemic lymphadenopathy and splenomegaly, severe autoimmune thrombocytopenia, and autoimmune neutropenia. Bone marrow examination and lymph node biopsy excluded the possibility of malignant lymphoma. Based on laboratory findings, he was finally diagnosed with combined autoimmune cytopenia coupled with SLE. Atypical clinical manifestations of SLE prompted us to explore the possibility of autoimmune lymphoproliferative syndrome (ALPS). However, we did not detect an increased number of CD4 - /CD8 - , CD3 + , TCRαβ + double-negative T cells in the circulating blood or dysfunctional T cell apoptosis in the Fas/Fas ligand pathway due to mutations in the FAS, FASLG or CASP10 genes. Combined autoimmune cytopenia is a rare clinical entity that in some cases co-occurs with other autoimmune diseases. Given that most SLE patients presenting atypical hematological manifestations at an early stage subsequently exhibit typical systemic manifestations, the present case raises the possibility that initial hematological abnormalities may be signs of unexpected SLE manifestations.

Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies

ClinicalTrials.gov

2017-12-03

Sickle Cell Disease; Transfusion Dependent Alpha- or Beta- Thalassemia; Diamond Blackfan Anemia; Paroxysmal Nocturnal Hemoglobinuria; Glanzmann Thrombasthenia; Severe Congenital Neutropenia; Shwachman-Diamond Syndrome; Non-Malignant Hematologic Disorders

Evaluation of the concomitant use of methotrexate and curcumin on Freund's complete adjuvant-induced arthritis and hematological indices in rats.

PubMed

Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Kumar, A Ranjith; Reddy, K Narsi

2011-09-01

To evaluate the concomitant administration of methotrexate and curcumin for antiarthiritic activity in rats. Arthritis was induced in rats following a single subplantar injection of Freund's complete adjuvant (0.1 ml). Rats were divided into six groups of six animals each. Group I and II were control injected with saline and Freund's complete adjuvant (0.1 ml), respectively. Group III arthritic rats were treated with curcumin (100 mg/kg, i.p.) on alternate days. Group IV received methotrexate (MTX) (2 mg/kg, i.p.) once in a week. Group-V and VI were treated with MTX (1 mg/kg, i.p.) once in a week and after 30 min received curcumin (30 mg/kg and 100 mg/kg, thrice a week, i.p.) from 10(th) to 45(th) days, respectively. Body weight and the paw volume was measured on 9(th), 16(th), 23(rd), 30(th), 37(th), and 45(th) days. Determination of complete blood cell counts, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration was determined on the 46(th) day. An improvement in body weight and a significant (P < 0.05) reduction in arthritis was observed with the combination treatment as compared to the positive control. A significant improvement in the hematological profile was also observed in rats treated with curcumin and methotrexate. The study showed a significant anti-arthritic action and protection from hematological toxicity with the combination treatment of methotrexate and curcumin.

Isoflurane is a suitable alternative to ether for anesthetizing rats prior to euthanasia for gene expression analysis.

PubMed

Nakatsu, Noriyuki; Igarashi, Yoshinobu; Aoshi, Taiki; Hamaguchi, Isao; Saito, Masumichi; Mizukami, Takuo; Momose, Haruka; Ishii, Ken J; Yamada, Hiroshi

2017-01-01

Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.

KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.

PubMed

Swords, Ronan T; Greenberg, Peter L; Wei, Andrew H; Durrant, Simon; Advani, Anjali S; Hertzberg, Mark S; Jonas, Brian A; Lewis, Ian D; Rivera, Gabriel; Gratzinger, Dita; Fan, Alice C; Felsher, Dean W; Cortes, Jorge E; Watts, Justin M; Yarranton, Geoff T; Walling, Jackie M; Lancet, Jeffrey E

2016-11-01

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nutritional status and hyperglycemia in the peritransplant period: a review of associations with parenteral nutrition and clinical outcomes.

PubMed

Verdi Schumacher, Marina; Moreira Faulhaber, Gustavo Adolpho

Hematopoietic stem cell transplantation is an established treatment option for various hematological diseases. This therapy involves complex procedures and is associated with several systemic complications. Due to the toxic effects of the conditioning regimen used in allogeneic transplantations, patients frequently suffer from severe gastrointestinal complications and are unable to feed themselves properly. This complex clinical scenario often requires specialized nutritional support, and despite the increasing number of studies available, many questions remain regarding the best way to feed these patients. Parenteral nutrition has been traditionally indicated when the effects on gastrointestinal mucosa are significant; however, the true benefits of this type of nutrition in reducing clinical complications have been questioned. Hyperglycemia is a common consequence of parenteral nutrition that seems to be correlated to poor transplantation outcomes and a higher risk of infections. Additionally, nutrition-related pre-transplantation risk factors are being studied, such as impaired nutritional status, poorly controlled diabetes mellitus and obesity. This review aims to discuss some of these recent issues. A real case of allogeneic transplant was used to illustrate the scenario and to highlight the most important topics that motivated this literature review. Copyright © 2017 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.

Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Philippe, Michael; Ranchon, Florence; Gilis, Lila; Schwiertz, Vérane; Vantard, Nicolas; Ader, Florence; Labussiere-Wallet, Hélène; Thomas, Xavier; Nicolini, Franck-Emmanuel; Wattel, Eric; Ducastelle-Leprêtre, Sophie; Barraco, Fiorenza; Lebras, Laure; Salles, Gilles; Michallet, Mauricette; Rioufol, Catherine

2016-04-01

After allogeneic hematopoietic stem cell transplantation (HSCT), BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication. Although supportive measures have been the standard of care for many years, several studies suggested the efficacy of cidofovir. The aim of this study was to assess the safety profile and efficacy of cidofovir. A retrospective study was conducted on all patients treated with cidofovir in our HSCT unit between March 2011 and May 2013. Data for efficacy (partial [PR] or complete response [CR]), prescription (dose, frequency, number of doses, and administration route), and toxicity were collected from published reports and medical files. Renal toxicity was evaluated using creatinine clearance calculated with the Cockcroft and Gault formula. A parallel literature search using PubMed (last search, May 2015) was performed. From March 2011 to June 2013, 27 of 181 patients undergoing allogeneic HSCT in our department received cidofovir for BKV-HC: 24 (88.9%) intravenously, 1 intravesically, and 2 via both routes. Mean dose was 5 mg/kg per administration, for a median of 4 injections (range, 1 to 11), from twice a week to once every 2 weeks. CR was achieved in 22 patients (81.5%), PR in 2, and no response in 2 patients. Eight patients presented renal failure (29.6%): 6 moderate (creatinine clearance < 60 mL/min) and 2 severe (creatinine clearance < 30 mLmin). Mean decrease in creatinine clearance after cidofovir was 27% (35 mL/min; range, 2 to 159). In 3 cases renal insufficiency and hematologic toxicity led to discontinuation of treatment or switch to intravesical instillation. For 3 patients cidofovir dose was reduced because of nephrotoxicity. Thirteen studies have reported on the use of cidofovir for BKV-HC (204 patients) since 2005. Intravenous cidofovir was used for 91.3% of patients, with doses ranging from .5 to 5 mg/kg. The main toxicity reported was renal failure (9% to 50% in 9 studies). Between 60% and 100% of CRs were observed independently of cidofovir dose or administration route. Cidofovir is an effective therapy for BKV-HC but requires very precise renal function management to avoid toxicity. Cidofovir treatment modalities (high dose, intravesical instillation, or low dose [≤1 mg/kg]) needs to be investigated in randomized controlled trials. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

PubMed Central

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD. PMID:27148267

Hematologic evaluation of employees with leukopenia. Naval Weapons Center, China Lake, California.

PubMed

Luiken, G A; Marsh, W L; Heath, V C; Long, H L; Weatherly, T L; Seal, G M

1988-12-01

Evaluation of 86 employees with a history of leukopenia at the Naval Weapons Center (NWC), China Lake, California, was done by exposure questionnaires, medical histories, physical examinations, peripheral blood smear, and bone marrow evaluations, including morphologic examination, stem cell culture, and cytogenetics. Forty-eight subjects were found to be leukopenic at the time of the study, and two subjects were found to have hairy cell leukemia. All subjects had positive exposure histories and were healthy at the time of the study. Review of peripheral smears identified the patients with marrow abnormalities. Bone marrow cultures revealed several patients with possible marrow suppression. Chromosome studies were not diagnostic. Five-year follow-up health questionnaires revealed no significant health problems; the two workers with hairy cell leukemia are alive and fully functional. Leukopenia in itself does not appear to be a risk factor for poor health, and it is unknown whether or not it may be a useful screening tool to identify workers at risk in toxic environments. Careful evaluation of blood cell counts and peripheral smears should be sufficient to identify people with potential marrow abnormalities.

Laboratory for Energy-Related Health Research: Annual report, fiscal year 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abell, D.L.

1989-04-01

The laboratory's research objective is to provide new knowledge for an improved understanding of the potential bioenvironmental and occupational health problems associated with energy utilization. Our purpose is to contribute to the safe and healthful development of energy resources for the benefit of mankind. This research encompasses several areas of basic investigation that relate to toxicological and biomedical problems associated with potentially toxic chemical and radioactive substances and ionizing radiation, with particular emphasis on carcinogenicity. Studies of systemic injury and nuclear-medical diagnostic and therapeutic methods are also involved. This program is interdisciplinary; it involves physics, chemistry, environmental engineering, biophysics andmore » biochemistry, cellular and molecular biology, physiology, immunology, toxicology, both human and veterinary medicine, nuclear medicine, pathology, hematology, radiation biology, reproductive biology, oncology, biomathematics, and computer science. The principal themes of the research at LEHR center around the biology, radiobiology, and health status of the skeleton and its blood-forming constituents; the toxicology and properties of airborne materials; the beagle as an experimental animal model; carcinogenesis; and the scaling of the results from laboratory animal studies to man for appropriate assessment of risk.« less

A phase 2 study of ofatumumab (Arzerra®) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL).

PubMed

Chen, Christine I; Paul, Harminder; Le, Lisa W; Wei, Ellen N; Snitzler, Susi; Wang, Trina; Levina, Olga; Kakar, Sumeet; Lau, Anthea; Queau, Michelle; Johnston, James B; Smith, Deborah A; Trudel, Suzanne

2018-06-19

AKT plays a centralized role in tumor proliferation and survival and is aberrantly activated in chronic lymphocytic leukemia (CLL). In this phase 2 trial, 30 relapsed/refractory CLL patients were treated with combination afuresertib, a novel oral AKT inhibitor, and ofatumumab for 6 months, followed by afuresertib maintenance for 12 months. We aimed to achieve deeper and more durable responses, without requiring long-term continuous treatment. Treatment was generally well tolerated but respiratory infections were common, with 18% severe requiring hospitalization. Hematologic toxicities were manageable (grade 3-4 neutropenia 39%). At a median follow-up of 13.4 months, overall responses were 50% (complete responses 3.6%). Median progression-free survival was 8.5 months and overall survival 34.8 months. Combination therapy with ofatumumab and afuresertib is active and well tolerated, but does not appear to lead to durable responses and may not provide additional benefit over single-agent ofatumumab in relapsed/refractory CLL. Novel agent combinations are currently undergoing intense investigation.

Toxicological and radiological safety of chicken meat irradiated with 7.5 MeV X-rays

NASA Astrophysics Data System (ADS)

Song, Beom-Seok; Lee, Yunjong; Park, Jong-Heum; Kim, Jae-Kyung; Park, Ha-Young; Kim, Dong-Ho; Kim, Chang-Jong; Kang, Il-Jun

2018-03-01

This study was conducted to evaluate the toxicological and radiological safety of chicken meat that had been irradiated at 30 kGy with 7.5 MeV X-rays. In a sub-chronic toxicity study, ICR mice were fed X-ray-irradiated chicken meat at 2500 mg/kg body weight daily for 90 days, and no mortality or abnormal clinical signs were observed throughout the study period. However, several hematological and serum biochemical parameters of the ICR mice differed significantly from those in the control group; nevertheless, the observed values were all within the normal range for the respective parameters. In addition, no toxicological effects were determined in male or female mice. Furthermore, no differences in gamma-ray spectrometric patterns were detected between the non-irradiated and irradiated samples, indicating that the radioactivity induced by 7.5 MeV X-ray irradiation was below the detection limit. These results tentatively suggest that chicken meat irradiated with 7.5 MeV X-rays would be safe for human consumption in terms of toxicology and radiology.

A pre-clinical safety study of PEGylated recombinant human endostatin (M2ES) in Sprague Dawley rats.

PubMed

Geng, Xingchao; Guo, Lifang; Liu, Li; Wang, Chao; Peng, Qian; Qi, Weihong; Sun, Li; Liu, Xiaomeng; Miao, Yufa; Lin, Zhi; Fu, Yan; Luo, Yongzhang; Li, Bo

2018-06-01

PEGylated recombinant human endostatin (M 2 ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A pre-clinical study was performed to evaluate the safety of M 2 ES in rats. After intravenous (IV) infusions of M 2 ES at a dose level of 3, 15 and 75 mg/kg in Sprague Dawley (SD) rats, M 2 ES was well tolerated in animals, with no observable changes in clinical observation, body weight, food consumption, urine analysis, hematology and serum biochemical analysis. The increase of kidney weights, and slight to severe vacuolation and necrosis of proximal tubule epithelial cells in kidney were observed in 15 and 75 mg/kg M 2 ES groups, but this adverse-effect was reversible. In summary, the major toxicity target organ of M 2 ES might be kidney, and the no observed adverse effect level (NOAEL) of M 2 ES in rats was 3 mg/kg in this study. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. Copyright © 2018. Published by Elsevier Inc.

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation.

PubMed

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD.

The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

PubMed Central

Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

2015-01-01

Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

Bone marrow monosomy 7: hematologic and clinical manifestations in childhood and adolescence.

PubMed

Hutter, J J; Hecht, F; Kaiser-McCaw, B; Hays, T; Baranko, P; Cohen, J; Durie, B

1984-01-01

The hematologic manifestations and clinical course are described for six children and adolescents with bone marrow monosomy 7. One child with secondary acute myelogenous leukemia had monosomy 7 plus a marker chromosome; the remaining patients had marrow monosomy 7 as the only karyotypic abnormality. The hematologic abnormalities were diverse, but the majority of patients had a smoldering preleukemic or myeloproliferative phase. Leukemic blasts were either undifferentiated or demonstrated evidence of myeloid differentiation. All patients responded poorly to antileukemic therapy. Bone marrow monosomy 7 was observed in one patient with severe marrow hypoplasia. Antileukemic therapy in another patient with greater than 30 per cent marrow blasts was associated with the development of a bone marrow myeloproliferative disorder with persistence of the monosomy 7 karyotype. We speculate that monosomy 7 may be a specific marker for a pluripotent hematopoietic stem cell abnormality that is associated with either blastic leukemia or a myeloproliferative disorder.

Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies.

PubMed

Grant, Steven

2018-06-01

Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future.

Toxicity Assessment of Wild Mushrooms from the Western Ghats, India: An in Vitro and Sub-Acute in Vivo Study

PubMed Central

Sai Latha, S.; Naveen, S.; Pradeep, C. K.; Sivaraj, C.; Dinesh, M. G.; Anilakumar, K. R.

2018-01-01

Background: Poisoning by different kinds of toxic mushrooms is unfortunately becoming an increasingly important medical problem, evident from the growing number of reports worldwide since the 1950s. Mycetism being a health concern, deserves scientific attention. In this perspective, the present study aims to assess the potential effects of ingesting the selected wild mushrooms from regions of the Western Ghats, India. Methods: The preliminary cytotoxicity of the selected mushrooms was studied in vitro on the intestinal NCM460 and the Chang's liver cell lines on the basis of cell viability. Further, the hepatotoxicity was assessed by measuring biologically relevant endpoints such as membrane integrity, mitochondrial stress and oxidative status. A 28 day sub-acute toxicity study was carried out by orally administering the mushroom extracts to mice at 250 and 500 mg/kg body weight. The hematological and serum analysis as well as histological examinations were carried out to evaluate their in vivo toxicity. GC-MS analysis of the mushrooms facilitated the identification of their volatile chemical profile. Result: The in vitro intestinal cytotoxicity exhibited by these wild mushrooms in comparison to the edible mushroom indicated their potential gastrointestinal toxicity. The pathological findings in small intestine on exposure to Chlorophyllum molybdites and Agaricus endoxanthus also validates the speculations about their intestinal toxicity. The toxic insult to the hepatocytes due to Amanita angustilamellata, Entoloma crassum, and Clarkeinda trachodes was predictive of the observed in vivo hepatotoxicity which was also accompanied by renal toxicity at the higher dose of 500 mg/kg bwt. Conclusion: The potential toxicity exhibited by these representative mushrooms from the wild warrants caution about their consumption. The present work could also have broader implications for global mycetism. PMID:29487528

Development and characterization of hyaluronic acid decorated PLGA nanoparticles for delivery of 5-fluorouracil.

PubMed

Yadav, Awesh K; Agarwal, Abhinav; Rai, Gopal; Mishra, Pradeep; Jain, Sanyog; Mishra, Anil K; Agrawal, Himanshu; Agrawal, Govind P

2010-11-01

The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of 99m Tc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.

Toxicity of Single-dose Intramuscular Injection of Samjeong Pharmacopuncture in Sprague-Dawley Rats.

PubMed

Kwon, Kang; Kim, Chul-Yun; Kim, Nam-Kwen; Sun, Seung-Ho; Seo, Hyung-Sik

2015-06-01

This study was carried out in order to find both the single-dose intramuscular injection toxicity and the approximate lethal dose of samjeong pharmacopuncture (SP) in Sprague-Dawley (SD) rats. The SD rats in this study were divided into four groups, one control group (1.0 mL/animal, normal saline) and three experimental groups (0.25, 0.5, and 1.0 mL/animal, SP). All groups consisted of five male and five female rats. SP was injected as a single-dose intramuscularly at the thigh. After the injection, general symptoms and weight were observed for 14 days. After the observations had ended, hematologic and serum biochemical examinations, necropsy and a local tolerance test at the injection site were performed. The experiments were carried out at the Good Laboratory Practice firm, Biotoxtech Co. (Cheongwon, Chungbuk). Animal experiments were approved by the Ethics Committee (Approval Number: 130379). No deaths occurred in any of the three experimental groups. The injection of SP had no effects on the general symptoms, body weights, results of the hematologic, and serum biochemical examinations, and necropsy findings. In local tolerance tests at the injection sites, mild inflammation was observed in the experimental group, but it did not appear to be a treatment related effect. Under the conditions of this test, the results from the injection of SP suggest that the approximate lethal dose of SP is above 1.0 mL/animal for both male and female SD rats. Therefore, the clinical use of SP is thought to be safe.

Acute, subacute toxicity and mutagenic effects of anacardic acids from cashew (Anacardium occidentale Linn.) in mice.

PubMed

Carvalho, Ana Laura Nicoletti; Annoni, Raquel; Silva, Paula Regina Pereira; Borelli, Primavera; Fock, Ricardo Ambrósio; Trevisan, Maria Teresa Salles; Mauad, Thais

2011-06-01

Anacardium occidentale Linn. (cashew) is a Brazilian plant that is usually consumed in natura and is used in folk medicine. Anacardic acids (AAs) in the cashew nut shell liquid are biologically active as gastroprotectors, inhibitors of the activity of various deleterious enzymes, antitumor agents and antioxidants. Yet, there are no reports of toxicity testing to guarantee their use in vivo models. We evaluated AAs biosafety by measuring the acute, subacute and mutagenic effects of AAs administration in BALB/c mice. In acute tests, BALB/c mice received a single oral dose of 2000 mg/kg, whereas animals in subacute tests received 300, 600 and 1000 mg/kg for 30 days. Hematological, biochemical and histological analyses were performed in all animals. Mutagenicity was measured with the acute micronucleus test 24h after oral administration of 250 mg/kg AAs. Our results showed that the AAs acute minimum lethal dose in BALB/c mice is higher than 2000 mg/kg since this concentration did not produce any symptoms. In subacute tests, females which received the highest doses (600 or 1000 mg/kg) were more susceptible, which was seen by slightly decreased hematocrit and hemoglobin levels coupled with a moderate increase in urea. Anacardic acids did not produce any mutagenic effects. The data indicate that doses less than 300 mg/kg did not produce biochemical and hematological alterations in BALB/c mice. Additional studies must be conducted to investigate the pharmacological potential of this natural substance in order to ensure their safe use in vivo. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Intravenous Single Dose Toxicity of Sweet Bee Venom in Sprague-Dawley Rats

PubMed Central

Lee, Kwang-Ho; Yu, JunSang; Sun, Seungho; Kwon, KiRok

2015-01-01

Objectives: Anaphylactic shock can be fatal to people who become hypersensitive when bee venom pharmacopuncture (BVP) is used. Thus, sweet bee venom (SBV) was developed to reduce these allergic responses. SBV is almost pure melittin, and SBV has been reported to have fewer allergic responses than BVP. BVP has been administered only into acupoints or intramuscularly, but we thought that intravenous injection might be possible if SBV were shown to be a safe medium. The aim of this study is to evaluate the intravenous injection toxicity of SBV through a single-dose test in Sprague-Dawley (SD) rats. Methods: Male and female 6-week-old SD rats were injected intravenously with SBV (high dosage: 1.0 mL/animal; medium dosage: 0.5 mL/animal; low dosage: 0.1 mL/animal). Normal saline was injected into the control group in a similar method. We conducted clinical observations, body weight measurements, and hematology, biochemistry, and histological observations. Results: No death was observed in any of the experimental groups. Hyperemia was observed in the high and the medium dosage groups on the injection day, but from next day, no general symptoms were observed in any of the experimental groups. No significant changes due to intravenous SBV injection were observed in the weights, in the hematology, biochemistry, and histological observations, and in the local tolerance tests. Conclusion: The results of this study confirm that the lethal dose of SBV is over 1.0 mL/animal in SD rats and that the intravenous injection of SBV is safe in SD rats. PMID:26389001

Disruption of erythrocyte antioxidant defense system, hematological parameters, induction of pro-inflammatory cytokines and DNA damage in liver of co-exposed rats to aluminium and acrylamide.

PubMed

Ghorbel, Imen; Maktouf, Sameh; Kallel, Choumous; Ellouze Chaabouni, Semia; Boudawara, Tahia; Zeghal, Najiba

2015-07-05

The individual toxic effects of aluminium and acrylamide are well known but there are no data on their combined effects. The present study was undertaken to determine (i) hematological parameters during individual and combined chronic exposure to aluminium and acrylamide (ii) correlation of oxidative stress in erythrocytes with pro-inflammatory cytokines expression, DNA damage and histopathological changes in the liver. Rats were exposed to aluminium (50 mg/kg body weight) in drinking water and acrylamide (20 mg/kg body weight) by gavage, either individually or in combination for 3 weeks. Exposure rats to AlCl3 or/and ACR provoked an increase in MDA, AOPP, H2O2 and a decrease in GSH and NPSH levels in erythrocytes. Activities of catalase, glutathione peroxidase and superoxide dismutase were decreased in all treated rats. Our results showed that all treatments induced an increase in WBC, erythrocyte osmotic fragility and a decrease in RBC, Hb and Ht. While MCV, MCH, MCHC remained unchanged. Hepatic pro-inflammatory cytokines expression including tumor necrosis factor-α, interleukin-6, interleukin-1β was increased suggesting leucocytes infiltration in the liver. A random DNA degradation was observed on agarose gel only in the liver of co-exposed rats to AlCl3 and ACR treatment. Interestingly, co-exposure to these toxicants exhibited synergism based on physical and biochemical variables in erythrocytes, pro-inflammatory cytokines and DNA damage in liver. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dose-volume effects for pelvic bone marrow in predicting hematological toxicity in prostate cancer radiotherapy with pelvic node irradiation.

PubMed

Sini, Carla; Fiorino, Claudio; Perna, Lucia; Noris Chiorda, Barbara; Deantoni, Chiara Lucrezia; Bianchi, Marco; Sacco, Vincenzo; Briganti, Alberto; Montorsi, Francesco; Calandrino, Riccardo; Di Muzio, Nadia; Cozzarini, Cesare

2016-01-01

To prospectively identify clinical/dosimetric predictors of acute/late hematologic toxicity (HT) in chemo-naÏve patients treated with whole-pelvis radiotherapy (WPRT) for prostate cancer. Data of 121 patients treated with adjuvant/salvage WPRT were analyzed (static-field IMRT n=19; VMAT/Rapidarc n=57; Tomotherapy n=45). Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral, lower and whole pelvis (WP), and the relative DVHs were calculated. HT was graded both according to CTCAE v4.03 and as variation in percentage relative to baseline. Logistic regression was used to analyze association between HT and clinical/DVHs factors. Significant differences (p<0.005) in the DVH of BM volumes between different techniques were found: Tomotherapy was associated with larger volumes receiving low doses (3-20 Gy) and smaller receiving 40-50 Gy. Lower baseline absolute values of WBC, neutrophils and lymphocytes (ALC) predicted acute/late HT (p ⩽ 0.001). Higher BM V40 was associated with higher risk of acute Grade3 (OR=1.018) or late Grade2 lymphopenia (OR=1.005). Two models predicting lymphopenia were developed, both including baseline ALC, and BM WP-V40 (AUC=0.73) and IL-V40+smoking (AUC=0.904) for acute/late respectively. Specific regions of pelvic BM predicting acute/late lymphopenia, a risk factor for viral infections, were identified. The 2-variable models including specific constraints to BM may help reduce HT. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of chronic ingestion of lead on gastrointestinal transit in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walsh, C.T.; Ryden, E.B.

1984-09-30

GI symptoms such as constipation and abdominal colic are signs of lead poisoning in man, but mechanisms of these effects have not been elucidated. To evaluate GI transit, male Wistar rats were dosed with 1% lead or 0.7% sodium acetate in their diet (AIN-76A). After 7 weeks, lead-treated animals exhibited decreased hematocrit, increased 24-hr urinary excretion of delta-ALA, increased kidney/body weight ratio, and decreased body weight. Blood-lead concentrations were elevated to 196 +/- 57 micrograms/dl. Lead treatment, however, did not result in change in GI transit of a nonabsorbable marker, 51Cr, 15 min or 6 hr after po administration. Theremore » was also no change in fecal percentage water content. Since in control animals the semipurified diet AIN-76A markedly decreased fecal excretion rate of 51Cr compared to a cereal-based diet, NIH-07, the latter was used in subsequent experiments. Rats fed 2 or 4% lead acetate in NIH-07 for 8 weeks exhibited renal and hematologic toxicity as in the initial experiment. Weight gain was impaired in the 4% group compared to pair-fed controls. No significant differences were observed in the 1-hr gastric emptying or the fecal excretion of 51Cr in the 2 or 4% lead-treated animals, although there was a trend for slower transit in rats receiving the higher dose. These observations indicate that concentrations of lead sufficient to induce renal and hematologic toxicity in rats do not substantially affect GI transit.« less

Neurological failure in ICU patients with hematological malignancies: A prospective cohort study.

PubMed

Marzorati, Chiara; Mokart, Djamel; Pène, Frederic; Lemiale, Virginie; Kouatchet, Achille; Mayaux, Julien; Vincent, François; Nyunga, Martine; Bruneel, Fabrice; Rabbat, Antoine; Lebert, Christine; Perez, Pierre; Benoit, Dominique; Citerio, Giuseppe; Azoulay, Elie; Legriel, Stephane

2017-01-01

Epidemiological studies of neurological complications in patients with hematological malignancies are scant. The objective of the study was to identify determinants of survival in patients with hematological malignancy and neurological failure. Post hoc analysis of a prospective study of adults with hematological malignancies admitted for any reason to one of 17 university or university-affiliated participating ICUs in France and Belgium (2010-2012). The primary outcome was vital status at hospital discharge. Of the 1011 patients enrolled initially, 226 (22.4%) had neurological failure. Presenting manifestations were dominated by drowsiness or stupor (65%), coma (32%), weakness (26%), and seizures (19%). Neuroimaging, lumbar puncture, and electroencephalography were performed in 113 (50%), 73 (32%), and 63 (28%) patients, respectively. A neurosurgical biopsy was done in 1 patient. Hospital mortality was 50%. By multivariate analysis, factors independently associated with higher hospital mortality were poor performance status (odds ratio [OR], 3.99; 95%CI, 1.82-9.39; P = 0.0009), non-Hodgkin's lymphoma (OR, 2.60; 95%CI, 1.35-5.15; P = 0.005), shock (OR, 1.95; 95%CI, 1.04-3.72; P = 0.04), and respiratory failure (OR, 2.18; 95%CI, 1.14-4.25; P = 0.02); and factors independently associated with lower hospital mortality were GCS score on day 1 (OR, 0.88/point; 95%CI, 0.81-0.95; P = 0.0009) and autologous stem cell transplantation (OR, 0.25; 95%CI, 0.07-0.75; P = 0.02). In ICU patients with hematological malignancies, neurological failure is common and often fatal. Independent predictors of higher hospital mortality were type of underlying hematological malignancy, poor performance status, hemodynamic and respiratory failures, and severity of consciousness impairment. Knowledge of these risk factors might help to optimize management strategies.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

PubMed

Alvarez, Edwin A; Wolfson, Aaron H; Pearson, J Matt; Crisp, Meredith P; Mendez, Luis E; Lambrou, Nicholas C; Lucci, Joseph A

2009-05-01

This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).

Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience.

PubMed

Moreno, Lucas; Vaidya, Sucheta J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Machin, David; Pearson, Andrew D J

2013-07-01

Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial. Copyright © 2012 Wiley Periodicals, Inc.

High-resolution melting analysis of sequence variations in the cytidine deaminase gene (CDA) in patients with cancer treated with gemcitabine.

PubMed

Raynal, Caroline; Ciccolini, Joseph; Mercier, Cédric; Boyer, Jean-Christophe; Polge, Anne; Lallemant, Benjamin; Mouzat, Kévin; Lumbroso, Serge; Brouillet, Jean-Paul; Evrard, Alexandre

2010-02-01

Gemcitabine (2',2'-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.

Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

PubMed

Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

2016-01-08

The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

A preliminary 13-week oral toxicity study of ginger oil in male and female Wistar rats.

PubMed

Jeena, Kottarapat; Liju, Vijayastelter B; Kuttan, Ramadasan

2011-12-01

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).

Crisis management in the treatment of childhood acute lymphoblastic leukemia: putting right what can go wrong (emergency complications of disease and treatment).

PubMed

Hough, Rachael; Vora, Ajay

2017-12-08

The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. The risk of relapse has been reduced to such an extent that the risk of treatment-related mortality is now approaching that of mortality caused by relapse. Toxicities may also lead to the suboptimal delivery of chemotherapy (treatment delays, dose reductions, dose omissions), potentially increasing relapse risk, and short- and long-term morbidity, adding to the "burden of therapy" in an increasing number of survivors. Thus, the need to reduce toxicity in pediatric ALL is becoming increasingly important. This work focuses on the risk factors, pathogenesis, clinical features, and emergency management of the life-threatening complications of ALL at presentation and during subsequent chemotherapy, including leucostasis, tumor lysis syndrome, infection, methotrexate encephalopathy, thrombosis, and pancreatitis. Potential strategies to abrogate these toxicities in the future are also discussed. © 2016 by The American Society of Hematology. All rights reserved.

Toxicological study on MUNOPHIL, water extract of Panax ginseng and Hericium erinaceum in rats.

PubMed

Park, Il-Dong; Yoo, Hwa-Seung; Lee, Yeon-Weol; Son, Chang-Gue; Kwon, Min; Sung, Ha-Jung; Cho, Chong-Kwan

2008-12-01

As data on the safety profile of Panax ginseng and Hericium erinaceum is lacking, the safety of these two compounds was examined in a series of toxicological studies. MUNOPHIL, the water extract mixture of Panax ginseng and Hericium erinaceum was tested in an oral subchronic 28-day toxicity study in rats at doses of 1250, 2500 and 5000 mg/kg/day. In repeated dose toxicity studies, no mortality was observed when varying doses of the extracts were administered once daily for a period of 28 days. There were no significant differences in body weight, absolute and relative organ weights between controls and treated rats of both sexes. Hematological analysis showed no differences in most parameters examined. In the biochemistry parameter analysis, no significant change occurred. Pathologically, neither gross abnormalities nor histopathological changes were observed. Therefore, MUNOPHIL appears to be safe and non-toxic in these studies and a no-observed adverse effect level in rats was established at 5000 mg/kg/day. The data could provide satisfactory preclinical evidence of safety to launch clinical trials on standardized formulation of plant extracts.

Studies on battery repair and recycling workers occupationally exposed to lead in Karachi.

PubMed

Haider, Muhammad Jamal; Qureshi, Naeemullah

2013-01-01

OBJECTIVE. The present study was carried out to investigate the effects of occupational lead exposure on the hematological and biochemical parameters in occupationally exposed and non exposed inhabitants of Karachi. MATERIAL AND METHODS. In 100 lead exposed subjects recruited from automobile workshops, lead battery repair and recycling units located in Karachi and in 100 control subjects the general health status, hematological parameters and exposure markers for lead were measured. RESULTS. Results indicated that the mean values of blood lead level and delta-aminolevulinic acid were significantly higher (P<0.05) while the activity of delta-aminolevulinic acid dehydratase were significantly decreased (P<0.05) among battery repair and recycling workers as compared to controls. The abnormalities in the blood lead level, delta-aminolevulinic acid and delta-aminolevulinic acid dehydratase were more frequent in lead exposed battery repair workers when compared with control subjects. The blood lead levels and deltaaminolevulinic acid were positively correlated while delta-aminolevulinic acid dehydratase was found to be negatively correlated with age, years of exposure and years of employment. Blood lead level was positively correlated with hemoglobin and RBC count while delta-aminolevulinic acid dehydratase was negatively correlated with hemoglobin concentration. The work related symptoms, droopiness, nasal symptoms and muscular pain were more frequent among battery repair workers as compared to control group. The findings of present study confirmed that occupational exposure to lead is associated with deviation in important hematological parameters and biological markers of exposure to lead among lead exposed workers, and also confirms the impact of lead exposure in the development of adverse effects among lead exposed workers. The study provides the data for risk assessment in lead battery repair workers of Karachi and suggests the need for preventive measures for battery repair workers and improvements to reduce occupational lead exposures to protect them from lead toxicity. It is suggested that hematological and physical examinations of lead exposed workers should be carried out periodically to prevent future health hazards.

Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma.

PubMed

Bradley, Jeffrey; Graham, Mary V; Winter, Kathryn; Purdy, James A; Komaki, Ritsuko; Roa, Wilson H; Ryu, Janice K; Bosch, Walter; Emami, Bahman

2005-02-01

To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer. A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V(20). The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50-78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure. The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.

Ninety-day oral toxicity study of rice-derived γ-oryzanol in Sprague-Dawley rats.

PubMed

Moon, Seol-Hee; Kim, Duyeol; Shimizu, Norihito; Okada, Tadashi; Hitoe, Shoketsu; Shimoda, Hiroshi

2017-01-01

A 90-day oral toxicity study of γ-oryzanol, a rice-derived triterpenoid ferulate, was performed by oral gavage administration to male and female Sprague-Dawley rats at doses of 0, 1000, and 2000 mg/kg body weight/day. All rats administered γ-oryzanol survived throughout the study period. Both male and female rats showed no toxicologically significant changes of the general signs, examination findings, body weight, food consumption, functional observational battery results, ophthalmological findings, urinalysis, hematology tests, clinical chemistry tests, organ weights, and necropsy findings. Moreover, there were no histopathological changes related to administration of γ-oryzanol in males and females from the 2000 mg/kg body weight/day group. In conclusion, the no observed adverse effect level (NOAEL) of γ-oryzanol exceeded 2000 mg/kg body weight/day for both male and female rats under the conditions of this study.

Safety assessment of lepidopteran insect-protected transgenic rice with cry2A* gene.

PubMed

Zou, Shiying; Huang, Kunlun; Xu, Wentao; Luo, Yunbo; He, Xiaoyun

2016-04-01

Numerous genetically modified (GM) crops expressing proteins for insect resistance have been commercialized following extensive testing demonstrating that the foods obtained from them are as safe as that obtained from their corresponding non-GM varieties. In this paper, we report the outcome of safety studies conducted on a newly developed insect-resistant GM rice expressing the cry2A* gene by a subchronic oral toxicity study on rats. GM rice and non-GM rice were incorporated into the diet at levels of 30, 50, and 70% (w/w), No treatment-related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. These results demonstrate that the GM rice with cry2A* gene is as safe for food as conventional non-GM rice.

Pharmacogenomics and histone deacetylase inhibitors

PubMed Central

Goey, Andrew KL; Sissung, Tristan M; Peer, Cody J; Figg, William D

2016-01-01

The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping. PMID:27767376

Nanoparticles Made From Xyloglucan-Block-Polycaprolactone Copolymers: Safety Assessment for Drug Delivery.

PubMed

Mazzarino, Letícia; Loch-Neckel, Gecioni; Dos Santos Bubniak, Lorena; Ourique, Fabiana; Otsuka, Issei; Halila, Sami; Curi Pedrosa, Rozangela; Santos-Silva, Maria Cláudia; Lemos-Senna, Elenara; Curti Muniz, Edvani; Borsali, Redouane

2015-09-01

Xyloglucan-block-polycaprolactone (XGO-PCL) copolymer nanoparticles have been proposed as nanocarriers for drug delivery. However, the possible harmful effects of exposure to nanoparticles still remain a concern. Therefore, the aim of this study is to evaluate the potential toxicity of XGO-PCL nanoparticles using in vitro and in vivo assays. Cytotoxicity and genotoxicity studies were conducted on MRC-5 human fetal lung fibroblast cells upon exposure to XGO-PCL nanoparticles. No significant reduction in the cell viability and no DNA damage were observed at the different concentrations tested. Erythrocyte toxicity was assessed by the incubation of nanoparticles with human blood. XGO-PCL nanoparticles induced a hemolytic ratio of less than 1%, indicating good blood compatibility. Finally, the subacute toxicity of XGO-PCL nanoparticles (10 mg/kg/day) was evaluated in BALB/c mice when administered orally or intraperitoneally for 14 days. Results of the in vivo toxicity study showed no clinical signs of toxicity, mortality, weight loss, or hematological and biochemical alterations after treatment with nanoparticles. Also, microscopic analysis of the major organs revealed no histopathological abnormalities, corroborating the previous results. Thus, it can be concluded that XGO-PCL nanoparticles induced no effect indicative of toxicity, indicating their potential use as drug delivery systems. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

An evaluation of acute toxicity of colloidal silver nanoparticles.

PubMed

Maneewattanapinyo, Pattwat; Banlunara, Wijit; Thammacharoen, Chuchaat; Ekgasit, Sanong; Kaewamatawong, Theerayuth

2011-11-01

Tests for acute oral toxicity, eye irritation, corrosion and dermal toxicity of colloidal silver nanoparticles (AgNPs) were conducted in laboratory animals following OECD guidelines. Oral administration of AgNPs at a limited dose of 5,000 mg/kg produced neither mortality nor acute toxic signs throughout the observation period. Percentage of body weight gain of the mice showed no significant difference between control and treatment groups. In the hematological analysis, there was no significant difference between mice treated with AgNPs and controls. Blood chemistry analysis also showed no differences in any of the parameter examined. There was neither any gross lesion nor histopathological change observed in various organs. The results indicated that the LD(50) of colloidal AgNPs is greater than 5,000 mg/kg body weight. In acute eye irritation and corrosion study, no mortality and toxic signs were observed when various doses of colloidal AgNPs were instilled in guinea pig eyes during 72 hr observation period. However, the instillation of AgNPs at 5,000 ppm produced transient eye irritation during early 24 hr observation time. No any gross abnormality was noted in the skins of the guinea pigs exposed to various doses of colloidal AgNPs. In addition, no significant AgNPs exposure relating to dermal tissue changes was observed microscopically. In summary, these findings of all toxicity tests in this study suggest that colloidal AgNPs could be relatively safe when administered to oral, eye and skin of the animal models for short periods of time.

Green tea extract-induced lethal toxicity in fasted but not in nonfasted dogs.

PubMed

Wu, Kuei-Meng; Yao, Jiaqin; Boring, Daniel

2011-02-01

Recent chronic toxicity studies performed on green tea extracts in fasted dogs have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Key findings included necrosis of hepatic cells, gastrointestinal epithelia and renal tubules, atrophy of reproductive organs, atrophy and necrosis of hematopoietic tissues, and associated hematological changes. The polyphenol cachetins (a mixture of primarily epigallocatechin gallate [≥55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied. Conduct of the study in nonfasted dogs under the same testing conditions and dose levels showed unremarkable results. Assuming both studies were valid, at the identified no observed adverse effect levels (NOAEL) of each study, systemic exposures (based on area under the curve [AUC]) were actually lower in fasted than nonfasted dogs, suggesting that fasting may have rendered the target organ systems potentially more vulnerable to the effects of green tea extract. The toxicity mechanisms that produced lethality are not known, but the results are scientifically intriguing. Because tea drinking has become more popular in the United States and abroad, the mode of action and site of action of green tea extract-induced lethal toxicities during fasting and the role of other phytochemical components of Folia Camellia sinensis (including nonpolyphenol fractions, which are often consumed when whole-leaf products are presented) warrant further investigation.

Acute and subacute toxicity of the Carapa guianensis Aublet (Meliaceae) seed oil.

PubMed

Costa-Silva, J H; Lima, C R; Silva, E J R; Araújo, A V; Fraga, M C C A; Ribeiro E Ribeiro, A; Arruda, A C; Lafayette, S S L; Wanderley, A G

2008-03-28

Carapa guianensis (Meliaceae), known as Andiroba in Brazil, has been used by Amazon Rainforest indigenous communities for treatment of coughs, convulsions, skin diseases, arthritis, rheumatism, ear infections, to heal wounds and bruises and as an insect repellent. Carapa guianensis seed oil (SO) was evaluated for its acute and subacute toxicity (30 days) by the oral route in Wistar rats. In the acute toxicity test, SO (0.625-5.0g/kg, n=5/sex) did not produce any hazardous symptoms or deaths. The subacute treatment with SO (0.375, 0.75 and 1.5g/kg, n=10/group) failed to change body weight gain, food and water consumption. Hematological analysis showed no significant differences in any of the parameters examined. However, in the biochemical parameters, there was an increase in the alanine aminotransferase (ALT) serum level (29%) in the group SO 1.5g/kg. In addition, absolute and relative liver weights were increased at the doses of 0.75g/kg (23.4 and 19.1%) and 1.5g/kg (18.7 and 33.1%). In conclusion, acute and subacute administration of Carapa guianensis seed oil did not produce toxic effects in male Wistar rats. However, the increase in the ALT serum level and in both absolute and relative liver weights may indicate a possible hepatic toxicity.

Oral Toxicity and Intestinal Transport Mechanism of Colloidal Gold Nanoparticle-Treated Red Ginseng

PubMed Central

Bae, Song-Hwa; Yu, Jin; Go, Mi-Ran; Kim, Hyun-Jin; Hwang, Yun-Gu; Choi, Soo-Jin

2016-01-01

(1) Background: Application of nanotechnology or nanomaterials in agricultural food crops has attracted increasing attention with regard to improving crop production, quality, and nutrient utilization. Gold nanoparticles (Au-NPs) have been reported to enhance seed yield, germination rate, and anti-oxidant potential in food crops, raising concerns about their toxicity potential. In this study, we evaluated the oral toxicity of red ginseng exposed to colloidal Au-NPs during cultivation (G-red ginseng) in rats and their intestinal transport mechanism. (2) Methods: 14-day repeated oral administration of G-red ginseng extract to rats was performed, and body weight, hematological, serum biochemical, and histopathological values were analyzed. An in vitro model of human intestinal follicle-associated epithelium (FAE) and an intestinal epithelial monolayer system were used for intestinal transport mechanistic study. (3) Results: No remarkable oral toxicity of G-red ginseng extract in rats was found, and Au-NPs did not accumulate in any organ, although Au-NP transfer to G-red ginseng and some increased saponin levels were confirmed. Au-NPs were transcytozed by microfold (M) cells, but not by a paracellular pathway in the intestinal epithelium. (4) Conclusion: These findings suggest great potential of Au-NPs for agricultural food crops at safe levels. Further study is required to elucidate the functional effects of Au-NPs on ginseng and long-term toxicity. PMID:28335336

Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats.

PubMed

Choi, Jia; Ryu, Su-Jung; Kim, Kui-Jin; Kim, Hyung-Min; Chung, Hee-Chul; Lee, Boo-Yong

2018-01-20

Gelidium elegans extract (GEE) is derived from a red alga from the Asia-Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD) rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted <2 days. Therefore, the LD 50 of GEE is likely to be >5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

Acute and Cumulative Effects of Unmodified 50-nm Nano-ZnO on Mice.

PubMed

Kong, Tao; Zhang, Shu-Hui; Zhang, Ji-Liang; Hao, Xue-Qin; Yang, Fan; Zhang, Cai; Yang, Zi-Jun; Zhang, Meng-Yu; Wang, Jie

2018-01-02

Nanometer zinc oxide (nano-ZnO) is widely used in diverse industrial and agricultural fields. Due to the extensive contact humans have with these particles, it is crucial to understand the potential effects that nano-ZnO have on human health. Currently, information related to the toxicity and mechanisms of nano-ZnO is limited. The aim of the present study was to investigate acute and cumulative toxic effects of 50-nm unmodified ZnO in mice. This investigation will seek to establish median lethal dose (LD50), a cumulative coefficient, and target organs. The acute and cumulative toxicity was investigated by Karber's method and via a dose-increasing method, respectively. During the experiment, clinical signs, mortality, body weights, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. The LD50 was 5177-mg/kg·bw; the 95% confidence limits for the LD50 were 5116-5238-mg/kg·bw. It could be concluded that the liver, kidney, lung, and gastrointestinal tract were target organs for the 50-nm nano-ZnO acute oral treatment. The cumulative coefficient (K) was 1.9 which indicated that the cumulative toxicity was apparent. The results also indicated that the liver, kidney, lung, and pancrea were target organs for 50-nm nano-ZnO cumulative oral exposure and might be target organs for subchronic and chronic toxicity of oral administered 50-nm ZnO.

Size dependent biodistribution and toxicokinetics of iron oxide magnetic nanoparticles in mice

NASA Astrophysics Data System (ADS)

Yang, Lin; Kuang, Huijuan; Zhang, Wanyi; Aguilar, Zoraida P.; Xiong, Yonghua; Lai, Weihua; Xu, Hengyi; Wei, Hua

2014-12-01

In spite of the immense benefits from iron oxide magnetic nanoparticles (IOMNs), there is scanty information regarding their metabolic activities and toxicity in vivo. In this study, we investigated the size dependent in vivo biodistribution, toxicokinetics, and toxicity and gene expression changes of various sizes of carboxyl coated IOMNs (diameters of 10, 20, 30, and 40 nm). Our findings demonstrated that the various sizes of IOMNs accumulated primarily in the liver and spleen on the first day post-injection. Interestingly, size dependent biodistribution and transport were observed: the smallest IOMNs (10 nm) showed the highest uptake by the liver, whereas the largest IOMNs (40 nm) showed the highest uptake by the spleen. Moreover, the IOMNs with the smallest size (10 nm) were cleared faster from the liver and kidneys, but more readily entered the brain and the uterus. IOMNs with the largest size (40 nm) accumulated more readily but were easily eliminated in the spleen. However, the level of iron in the heart decreased in all IOMN exposed groups. In addition, blood biochemistry, hematological analyses and histological examination demonstrated that there was no apparent acute toxicity caused by IOMNs in mice. However, smaller IOMNs (10 nm and 20 nm) more effectively changed the expression level of sensitive genes related to oxidant stress, iron transport, metabolic process, apoptosis, and others.In spite of the immense benefits from iron oxide magnetic nanoparticles (IOMNs), there is scanty information regarding their metabolic activities and toxicity in vivo. In this study, we investigated the size dependent in vivo biodistribution, toxicokinetics, and toxicity and gene expression changes of various sizes of carboxyl coated IOMNs (diameters of 10, 20, 30, and 40 nm). Our findings demonstrated that the various sizes of IOMNs accumulated primarily in the liver and spleen on the first day post-injection. Interestingly, size dependent biodistribution and transport were observed: the smallest IOMNs (10 nm) showed the highest uptake by the liver, whereas the largest IOMNs (40 nm) showed the highest uptake by the spleen. Moreover, the IOMNs with the smallest size (10 nm) were cleared faster from the liver and kidneys, but more readily entered the brain and the uterus. IOMNs with the largest size (40 nm) accumulated more readily but were easily eliminated in the spleen. However, the level of iron in the heart decreased in all IOMN exposed groups. In addition, blood biochemistry, hematological analyses and histological examination demonstrated that there was no apparent acute toxicity caused by IOMNs in mice. However, smaller IOMNs (10 nm and 20 nm) more effectively changed the expression level of sensitive genes related to oxidant stress, iron transport, metabolic process, apoptosis, and others. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05061d

Epidemiology and treatment approaches in management of invasive fungal infections

PubMed Central

Kriengkauykiat, Jane; Ito, James I; Dadwal, Sanjeet S

2011-01-01

Over the past 20 years, the number of invasive fungal infections has continued to persist, due primarily to the increased numbers of patients subjected to severe immunosuppression. Despite the development of more active, less toxic antifungal agents and the standard use of antifungal prophylaxis, invasive fungal infections (especially invasive mold infections) continue to be a significant factor in hematopoietic cell and solid organ transplantation outcomes, resulting in high mortality rates. Since the use of fluconazole as standard prophylaxis in the hematopoietic cell transplantation setting, invasive candidiasis has come under control, but no mold-active antifungal agent (except for posaconazole in the setting of acute myelogenous leukemia and myelodysplastic syndrome) has been shown to improve the survival rate over fluconazole. With the advent of new azole and echinocandin agents, we have seen the emergence of more azole-resistant and echinocandin-resistant fungi. The recent increase in zygomycosis seen in the hematopoietic cell transplantation setting may be due to the increased use of voriconazole. This has implications for the empiric approach to pulmonary invasive mold infections when zygomycosis cannot be ruled out. It is imperative that an amphotericin B product, an antifungal that has never developed resistance in over 50 years, be initiated. The clinical presentations of invasive mold infections and invasive candidiasis can be nonspecific and the diagnostic tests insensitive, so a high index of suspicion and immediate initiation of empiric therapy is required. Unfortunately, our currently available serologic tests do not predict infection ahead of disease, and, therefore cannot be used to initiate “preemptive” therapy. Also, the Aspergillus galactomannan test gives a false negative result in patients receiving antimold prophylaxis, ie, virtually all of our patients with hematologic malignancy and hematopoietic cell transplant recipients. We may eventually be able to select patients at highest risk for invasive fungal infections for prophylaxis by genetic testing. However, with our current armamentarium of antifungal agents and widespread use of prophylaxis in high-risk groups (hematologic malignancy, hematopoietic cell transplantation), we continue to see high incidence and mortality rates, and our future hope lies in reversing the immunosuppression or augmenting the immune system of these severely immunocompromised hosts by developing and utilizing immunotherapy, immunoprophylaxis, and vaccines. PMID:21750627

A Literature Review - Problem Definition Studies on Selected Toxic Chemicals. Volume 4. Occupational Health and Safety Aspects of the Fog Oils SGF No. 1 and SGF No. 2 and Smoke Screens Generated from Them

DTIC Science & Technology

1978-04-01

deaths, no weight losses, and no abnormal hematological findings (8). b. Rabbits In groups of rabbits intermittently exposed to diesel fumes, Samal et al...lymphocyto- penia; watery bone marrow; dermatitis rabbits diesel fuel and motor reduced antibody produc- Samal I_ ,., oil fumes (100:6 mix- tion to...Laboratory Report No. 46, 1945. 91. Samal , U. C., R. Saran, R. K. Sanyal: Effects of inhaled fumes on immunological response of rabbits. Indian J Physiol

Concurrent chemoradiotherapy versus radiotherapy alone for locoregionally advanced nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy: a meta-analysis.

PubMed

He, Yan; Guo, Tao; Guan, Hui; Wang, Jingjing; Sun, Yu; Peng, Xingchen

2018-01-01

In this study, we attempted to compare the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with radiotherapy alone (RT) for locoregionally advanced nasopharyngeal carcinoma (LANPC) in the era of intensity-modulated radiotherapy (IMRT) by meta-analysis. We searched databases, and all randomized controlled trials meeting the inclusion criteria were utilized for a meta-analysis with RevMan 5.3 based on the Cochrane methodology. Fifteen studies were found suitable based on the inclusion criteria. CCRT not only significantly improved the overall response rate (risk ratio [RR]=0.53, 95% CI 0.43-0.66) and the complete response rate (RR=0.60, 95% CI 0.51-0.71) but also contributed to longer overall survival. The incidence of grade 3-4 adverse events from CCRT group increased in hematologic toxicity (RR 2.25, 95% CI 1.54-3.29), radiation-induced oral mucositis (RR 1.64, 95% CI 1.14-2.35), and radiodermatitis (RR 1.80, 95% CI 1.13-2.88). Compared with IMRT alone, CCRT provided survival benefit with acceptable toxicity in patients with LANPC. However, we need multicenter randomized controlled trials and long-term follow-up to evaluate the eventual efficacy and toxicity of concurrent chemotherapy plus IMRT.

Toxicological investigations on the methanol sub-fraction of the seeds of Carica papaya as a male contraceptive in albino rats.

PubMed

Lohiya, Nirmal K; Manivannan, Boomi; Garg, Shipra

2006-10-01

Pre-clinical acute and sub-chronic toxicity studies of the methanol sub-fraction (MSF) of the seeds of Carica papaya, a putative male contraceptive, have been investigated in rats to evaluate safety of the test substance. A single oral dose of MSF at 2000 mg/kg body weight was studied over 14 days for acute toxicity, and daily oral doses of 50, 100, 250 and 500 mg/kg body weight were studied for 28- and 90-day periods for sub-chronic toxicity. Body weight, food and water intake and phenotypical toxicological symptoms were recorded daily. Sperm analysis, hematology, serum clinical biochemistry, libido and pathological examination of vital organs were recorded at the termination of the experimental periods. We observed no overt general toxicity in exposed animals. Food and water intake showed daily fluctuations within control limits. Sperm density showed a significant decrease in all 28- and 90-day repeated dose treated animals whereas total sperm motility inhibition was observed at 250 and 500 mg/kg dose levels at the 28-day time interval but in all dose groups at the 90-day interval. The preliminary results suggest the test substance may be a safe approach to male anti-fertility.

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia.

PubMed

Zhao, Hongyu; Xu, Li; Yang, Yongjian; Shao, Jianhua; Chen, Ping; Dong, Xuebin; Gu, Linping; Li, Daqi

2017-01-01

To investigate the safety and efficacy of the triple therapy of decitabine, idarubicin, and cytarabine in the treatment of refractory or recurrent acute myeloid leukemia (R/R AML). We conducted a single-center retrospective study in which decitabine treatment was administered prior to full-dose idarubicin and cytarabine (D-IA) for 21 R/R AML patients. After 1 cycle of D-IA, 10/21 (47.6%) patients experienced a complete remission (CR) and 2/21 (9.5%) showed a partial response. There was a 1-month response rate (RR) in 12/21 patients (57.14%); these patients achieved CR after 2 cycles of D-IA. Five of these 12 (40%) patients then received sequential allogeneic stem cell transplantation. At the last follow-up date, 9/21 (42.8%) patients had survived, and 7/21 (33.3%) were in continuous CR. Hematological toxicity and infections were the most prominent toxicities of this regimen. Other toxicities included nausea, vomiting, bleeding, and liver enzyme abnormalities. No mortalities were recorded due to treatment-related toxicity during remission. The combination was well tolerated, and the RR was encouraging. Our study suggests that D-IA may offer a novel and potentially effective treatment regimen for R/R AML patients. © 2017 S. Karger AG, Basel.

Evaluation of Toxicity and Antimicrobial Activity of an Ethanolic Extract from Leaves of Morus alba L. (Moraceae)

PubMed Central

de Oliveira, Alisson Macário; Mesquita, Matheus da Silva; da Silva, Gabriela Cavalcante; de Oliveira Lima, Edeltrudes; de Medeiros, Paloma Lys; Paiva, Patrícia Maria Guedes; de Souza, Ivone Antônia; Napoleão, Thiago Henrique

2015-01-01

This work evaluated an ethanolic extract from Morus alba leaves for toxicity to Artemia salina, oral toxicity to mice, and antimicrobial activity. Phytochemical analysis revealed the presence of coumarins, flavonoids, tannins, and triterpenes in the extract, which did not show toxicity to A. salina nauplii. No mortality and behavioral alterations were detected for mice treated with the extract (300 and 2000 mg/kg b.w.) for 14 days. However, animals that received the highest dose showed reduced MCV and MCHC as well as increased serum alkaline phosphatase activity. In treatments with the extract at both 300 and 2000 mg/kg, there was a reduction in number of leukocytes, with decrease in percentage of lymphocytes and increase in proportion of segmented cells. Histopathological analysis of organs from mice treated with the extract at 2000 mg/kg revealed turgidity of contorted tubules in kidneys, presence of leukocyte infiltration around the liver centrilobular vein, and high dispersion of the spleen white pulp. The extract showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Candida krusei, Candida tropicalis, and Aspergillus flavus. In conclusion, the extract contains antimicrobial agents and was not lethal for mice when ingested; however, its use requires caution because it promoted biochemical, hematological, and histopathological alterations. PMID:26246840

Effect of aluminum (Al) speciation on erythrocytic antioxidant defense process: Correlations between lipid membrane peroxidation and morphological characteristics.

PubMed

Cheng, Dai; Tang, Jinlei; Wang, Xuerui; Zhang, Xinyu; Wang, Shuo

2018-08-15

Al contamination becomes a growing problem in human society. Accumulation of Al in blood could destroy the structure and disorder function of erythrocyte, and finally cause blood diseases. In the present study, AlCl 3 and Al(malt) 3 are respectively used in the erythrocyte system, in order to investigate the comparative toxic effect on erythrocyte fragility, the influence on cellular biochemical components and lipid peroxidation level. We find that the osmotic fragility, the number of Heinz bodies, the content of MDA and advanced oxidation protein product of the AlCl 3 treated erythrocytes were higher than the Al(malt) 3 treated erythrocytes at the same concentrations of Al(Ⅲ). The morphological and membrane protein changes of the AlCl 3 treated group show superior to the Al(malt) 3 treated group. In summary, we conclude that the comparative effect on the erythrocyte between organic aluminum and inorganic aluminum is significantly different, and the prime comparative difference between the toxic effects of both the compounds is oxidative stress. Further research should focus on in vivo experiments to confirm the differential toxicity and to elucidate the molecular mechanisms underlying Al-induced erythrocyte toxicity in order to prevent hematological disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Clinical and hematological presentation of children and adolescents with polycythemia vera.

PubMed

Cario, Holger; McMullin, Mary Frances; Pahl, Heike L

2009-08-01

Polycythemia vera (PV) in children and adolescents is very rare. Data on clinical and laboratory evaluations as well as on treatment modalities are sparse. Here, we report the long-term clinical course of a PV patient first diagnosed more than 40 years ago at age 12. In addition, after a systematic review of the scientific medical literature, clinical and hematological data of 35 patients (19 female and 17 male) from 25 previous reports are summarized. Three patients developed PV following antecedent hematological malignancies. Budd-Chiari syndrome was diagnosed in seven patients indicating a particular risk of young patients of developing this disorder. One patient presented with ischemic stroke, one patient with gangrene, and three patients with severe hemorrhage. Three patients died from disease-related complications. Hematocrit levels and platelet counts were not correlated with disease severity. Leukocytosis >15 x 10(9)/L was present in 9/35 patients and associated with a thromboembolic or hemorrhagic complication in seven patients. The few available data on molecular genetics and endogenous erythroid colony growth indicate changes comparable to those detectable in adult patients. Treatment varied enormously. It included aspirin, phlebotomy, hydroxycarbamide, busulfan, melphalan, pyrimethamine, and interferon-alpha. Two patients successfully underwent stem cell transplantation. Currently, it is impossible to treat an individual pediatric PV patient with an evidence-based regimen.

Hematology and erythrocyte osmotic fragility of the Franquet's fruit bat (Epomops franqueti).

PubMed

Ekeolu, Oyetunde Kazeem; Adebiyi, Olamide Elizabeth

2018-03-15

Hematological parameters are vital diagnostic tools for understanding health dynamics of humans and animals. Franquet's fruit bat (Epomops franqueti) is host to several parasites such as protozoa, bacteria, viruses and mites. Yet, studies exploring the values of its blood components with interest for research or food purposes are scarce. Thus, this study was carried out to investigate the hematological values of the adult E. franqueti. Seventeen (nine female and eight male) apparently healthy adult E. franqueti were captured from their roosting colony. Blood samples were collected for determination of erythrocyte indices [red blood cell count (RBC), packed cell volume (PCV), hemoglobin (Hb) concentration, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)] and leukocyte indices [total white blood cell counts (WBC), lymphocytes, eosinophil, monocytes, neutrophil count and erythrocytes osmotic fragility]. There were no significant (p≥0.05) sex-related differences in RBC, PCV, Hb concentration, MCV, MCH, MCHC and total and differential WBC of E. franqueti. Erythrocyte osmotic fragility was significantly higher in female than in male E. franqueti at 0.1% NaCl. These considerations are critical in establishing reference ranges of blood parameters for E. franqueti and may provide insight to why they serve as reservoir hosts for several microorganisms.

Clinical and hematological presentation of children and adolescents with polycythemia vera

PubMed Central

McMullin, Mary Frances; Pahl, Heike L.

2014-01-01

Polycythemia vera (PV) in children and adolescents is very rare. Data on clinical and laboratory evaluations as well as on treatment modalities are sparse. Here, we report the long-term clinical course of a PV patient first diagnosed more than 40 years ago at age 12. In addition, after a systematic review of the scientific medical literature, clinical and hematological data of 35 patients (19 female and 17 male) from 25 previous reports are summarized. Three patients developed PV following antecedent hematological malignancies. Budd–Chiari syndrome was diagnosed in seven patients indicating a particular risk of young patients of developing this disorder. One patient presented with ischemic stroke, one patient with gangrene, and three patients with severe hemorrhage. Three patients died from disease-related complications. Hematocrit levels and platelet counts were not correlated with disease severity. Leukocytosis >15×109/L was present in 9/35 patients and associated with a thromboembolic or hemorrhagic complication in seven patients. The few available data on molecular genetics and endogenous erythroid colony growth indicate changes comparable to those detectable in adult patients. Treatment varied enormously. It included aspirin, phlebotomy, hydroxycarbamide, busulfan, melphalan, pyrimethamine, and interferon-alpha. Two patients successfully underwent stem cell transplantation. Currently, it is impossible to treat an individual pediatric PV patient with an evidence-based regimen. PMID:19468728

Normal hematology and serum chemistry of northern fur seals (Callorhinus ursinus) in captivity.

PubMed

Kohyama, Kaoru; Inoshima, Yasuo

2017-09-01

Northern fur seals (Callorhinus ursinus) are endemic to the North Pacific Ocean. They were hunted for their fur and became endangered in the late 1800s, but their populations recovered following the introduction of protection laws. Recently, populations have been decreasing again, although the reasons are unclear. For individuals that are bred and reared in captivity as part of ex situ conservation projects, details of blood characteristics are essential to ensure good health. However, the normal ranges of hematology and serum chemistry of captive northern fur seals have not been defined. This study determined the normal ranges of hematology and serum chemistry of captive fur seals. Blood samples were collected every month for 2 years from four captive northern fur seals in Japan (three born in an aquarium and one kept in the same aquarium following rescue). Fifteen blood characteristics and 29 serum chemistry properties were compared with those previously reported for wild northern fur seals in the USA. Several parameters were not within the normal ranges reported previously in wild northern fur seals. In particular, levels of alkaline phosphatase was outside of the normal ranges previously reported. The hematological and serum chemistry ranges in this study can help provide a guideline for understanding the health of northern fur seals in captivity. © 2017 Wiley Periodicals, Inc.

Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors.

PubMed

Ghosh, Arnab; Politikos, Ioannis; Perales, Miguel-Angel

2017-11-01

For several decades, hematopoietic cell transplantation (HCT) has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of HCT are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, the role of HCT has evolved. Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autologous HCT. Checkpoint inhibitors are also being tested after allogeneic HCT with observable benefits in treating hematological malignancies, but with a potential risk of increased graft versus host disease and transplant-related mortality. Immunotherapy with Cluster of differentiation 19 CAR T cells are powerful options with aggressive B-cell malignancies both for therapy and as induction leading to allogeneic HCT. Although immunotherapies with checkpoint inhibition and CAR T cells are increasingly being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies.

Rapid COJEC versus standard induction therapies for high-risk neuroblastoma.

PubMed

Peinemann, Frank; Tushabe, Doreen A; van Dalen, Elvira C; Berthold, Frank

2015-05-19

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. In the rapid COJEC induction schedule, higher single doses of selected drugs than standard induction schedules are administered over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy and might improve survival. The aim of this study was to evaluate the efficacy and adverse events of the rapid COJEC induction schedule as compared to standard induction schedules in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Outcomes of interest were complete response, early toxicity and treatment-related mortality as primary endpoints and overall survival, progression- and event-free survival, late non-hematological toxicity, and health-related quality of life as secondary endpoints. We searched the electronic databases CENTRAL (2014, Issue 11), MEDLINE (PubMed), and EMBASE (Ovid) for articles from inception to 11 November 2014. Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages. Randomized controlled trials evaluating the rapid COJEC induction schedule for high-risk neuroblastoma patients compared to standard induction schedules. Two review authors performed study selection, abstracted data on study and patient characteristics, and assessed risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. We downgraded for risk of bias and imprecision We identified one randomized controlled trial (CCLG-ENSG-5) that included 262 patients with high-risk neuroblastoma who were randomized to receive either rapid COJEC (N = 130) or standard OPEC/COJEC (N = 132) induction chemotherapy. We graded the evidence as low quality; we downgraded for risk of bias and imprecision.There was no clear evidence of a difference between the treatment groups in complete response (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.71 to 1.38), treatment-related mortality (RR 1.21, 95% CI 0.33 to 4.39), overall survival (hazard ratio (HR) 0.83, 95% CI 0.63 to 1.10), and event-free survival (HR 0.86, 95% CI 0.65 to 1.13). We calculated the HRs using the complete follow-up period of the trial.Febrile neutropenia (two or more episodes), proven fungal infections, septicemia (one or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m(2)), neurological toxicity (grade 3 or 4), and ototoxicity (Brock grade 2 to 4) were addressed as early toxicities (during pre-operative chemotherapy). For febrile neutropenia, septicemia, and renal toxicity, a statistically significant difference in favor of the standard treatment arm was identified; for all other early toxicities no clear evidence of a difference between treatment groups was identified. With regard to late non-hematological toxicities (median follow-up 12.7 years; range 6.9 to 16.5 years), the study provided data on any complication, renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73m(2)), ototoxicity (Brock grade 1 to 4), endocrine complications, neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies. For endocrine complications and neurocognitive complications, a statistically significant difference in favor of the rapid COJEC arm was found; for all other late non-hematological toxicities no clear evidence of a difference between treatment groups was identified.Data on progression-free survival and health-related quality of life were not reported. We identified one randomized controlled trial that evaluated rapid COJEC versus standard induction therapy in patients with high-risk neuroblastoma. No clear evidence of a difference in complete response, treatment-related mortality, overall survival, and event-free survival between the treatment alternatives was found. This could be the result of low power or too short a follow-up period. Results of both early and late toxicities were ambiguous. Information on progression-free survival and health-related quality of life were not available. This trial was performed in the 1990s. Since then, many changes in, for example, treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of rapid COJEC and standard induction therapy in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy

PubMed Central

Williams, Brent A.; Law, Arjun Datt; Routy, Bertrand; denHollander, Neal; Gupta, Vikas; Wang, Xing-Hua; Chaboureau, Amélie; Viswanathan, Sowmya; Keating, Armand

2017-01-01

Background Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials. Materials and Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 109 cells/m2, 3 × 109 cells/m2 and 5 × 109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. Results Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial. Conclusions Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation. PMID:29179517

Melphalan-Based Reduced-Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Al Malki, Monzr M; Nathwani, Nitya; Yang, Dongyun; Armenian, Saro; Dadwal, Sanjeet; Salman, Jaroslava; Mokhtari, Sally; Cao, Thai; Sandhu, Karamjeet; Rouse, Michelle; Mei, Matthew; Ali, Haris; Parker, Pablo; Alvarnas, Joseph; Smith, Eileen; Donnell, Margaret O; Marcucci, Guido; Snyder, David; Nademanee, Auayporn; Forman, Stephen J; Stein, Anthony; Nakamura, Ryotaro

2018-05-09

Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the "semiablative" nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred-day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Epirubicin versus mitoxantrone in combination chemotherapy for metastatic breast cancer.

PubMed

Pavesi, L; Preti, P; Da Prada, G; Pedrazzoli, P; Poggi, G; Robustelli della Cuna, G

1995-01-01

As valid therapeutic alternatives to adriamycin, with a more favourable safety profile, epirubicin (E) and novantrone (N) were compared in combination with fluorouracil (F) and cyclophosphamide (C) in a prospective randomized clinical trial as first-line treatment for metastatic breast cancer (mbc). 158 women with mbc were randomly allocated to receive FEC or FNC regimen; the dosage in mg/m2 was as follows: 500 for C and F, 75 for E and 10 for N. All drugs were administered iv. on day 1 and recycled on day 21. In 141 evaluable patients the response rate (CR+PR) was better in the FEC (43.6%) than in the FNC regimen (30.3%) (95% C.I. of 32% to 55% versus 14% to 34%), without any statistically significant difference. Differences in response rate were significantly in favour of FEC group in previously untreated patients (57.6% versus 25%, p = .02), and in postmenopausal women (46.1% versus 23.6%, p = .01). No significant differences between the two treatment arms were observed in terms of either time to progression or duration of response and survival. The most important dose-limiting toxicity was hematological (leuko-and thrombocytopenia were significantly higher in FNC-treated patients). This difference in hematological toxicity sustained a significantly different incidence of delays in administering chemotherapy courses, which precluded the administration of comparable doses of all drugs in both groups. The incidence of complete alopecia was significantly higher in FEC-treated patients, while no clinical or instrumental evidence of CHF was observed with either regimen. Due to its more favourable therapeutic profile, the E-containing regimen seems a suitable first-line treatment for previously untreated patients with mbc, while the FNC combination should be offered to women refusing hair loss.

The effect of ZnO nanoparticles on liver function in rats

PubMed Central

Tang, Hua-Qiao; Xu, Min; Rong, Qian; Jin, Ru-Wen; Liu, Qi-Ji; Li, Ying-Lun

2016-01-01

Zinc oxide (ZnO) is widely incorporated as a food additive in animal diets. In order to optimize the beneficial effects of ZnO and minimize any resultant environmental pollution, ZnO nanoparticles are often used for delivery of the zinc. However, the possible toxic effects of ZnO nanoparticles, including effects on cytochrome P450 (CYP450) enzymes, have not been evaluated. In this study, we investigated the effect of ZnO nanoparticles, in doses used in animal feeds, on CYP450 enzymes, liver and intestinal enzymes, liver and kidney histopathology, and hematologic indices in rats. We found that liver and kidney injury occurred when the concentrations of ZnO nanoparticles in feed were 300–600 mg/kg. Also, liver mRNA expression for constitutive androstane receptor was suppressed and mRNA expression for pregnane X receptor was induced when feed containing ZnO nanoparticles was given at a concentration of 600 mg/kg. Although the expression of mRNA for CYP 2C11 and 3A2 enzymes was induced by ZnO nanoparticles, the activities of CYP 2C11 and 3A2 were suppressed. While liver CYP 1A2 mRNA expression was suppressed, CYP 1A2 activity remained unchanged at all ZnO nanoparticle doses. Therefore, it has been concluded that ZnO nanoparticles, in the doses customarily added to animal feed, changed the indices of hematology and blood chemistry, altered the expression and activity of hepatic CYP enzymes, and induced pathological changes in liver and kidney tissues of rats. These findings suggest that greater attention needs to be paid to the toxic effects of ZnO nanoparticles in animal feed, with the possibility that the doses of ZnO should be reduced. PMID:27621621

Continuous infusion of amphotericin B: preliminary experience at Faculdade de Medicina da Fundação ABC.

PubMed

Uehara, Roberto Palermo; Sá, Victor Hugo Lara de; Koshimura, Erika Tae; Prudente, Fernanda Vilas Boas; Tucunduva, Luciana Tomanik Cardozo de Mello; Gonçalves, Marina Sahade; Samano, Eliana Sueco Tibana; del Giglio, Auro

2005-09-01

Intravenous amphotericin B deoxycholate (AmB-D) infusions, usually given over 4 hours, frequently induce nephrotoxicity and undesirable infusion-related side effects such as rigors and chills. There is evidence in the literature that the use of AmB-D in the form of continuous 24-hour infusion is less toxic than the usual four-hour infusion of this drug. Our objective was to evaluate the efficacy and safety of continuous infusion of AmB-D for the treatment of persistent fever in neutropenic patients with hematological malignancies after chemotherapy. Observational retrospective analysis of our experience with continuous infusion of AmB-D, at Faculdade de Medicina da Fundação ABC and Hospital Estadual Mário Covas in Santo André. From October 2003 to May 2004, 12 patients with hematological malignancies and chemotherapy-induced neutropenia received 13 cycles of continuous infusion of AmB-D. The median dose of AmB-D was 0.84 mg/kg/day (0.33 to 2.30 mg/kg/day). Concomitant use of nephrotoxic medications occurred in 92% of the cycles. Nephrotoxicity occurred in 30.76% of the cycles, hypokalemia in 16.67%, hepatotoxicity in 30% and adverse infusion-related events in 23%. All patients survived for at least seven days after starting continuous infusion of AmB-D, and clinical resolution occurred in 76% of the cycles. Continuous infusion of AmB-D can be used in our Institution as an alternative to the more toxic four-hour infusion of AmB-D and possibly also as an alternative to the more expensive liposomal formulations of the drug.

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis ▿ §

PubMed Central

Cornely, O. A.; Vehreschild, J. J.; Vehreschild, M. J. G. T.; Würthwein, G.; Arenz, D.; Schwartz, S.; Heussel, C. P.; Silling, G.; Mahne, M.; Franklin, J.; Harnischmacher, U.; Wilkens, A.; Farowski, F.; Karthaus, M.; Lehrnbecher, T.; Ullmann, A. J.; Hallek, M.; Groll, A. H.

2011-01-01

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin. PMID:21911573

Clinical outcome and prognostic markers for patients with gynecologic malignancies in phase 1 clinical trials: a single institution experience from 1999 to 2010.

PubMed

Hou, June Y; Aparo, Santiago; Ghalib, Mohammad; Chaudhary, Imran; Shah, Umang; Swami, Umang; Einstein, Mark; Goldberg, Gary L; Mani, Sridhar; Goel, Sanjay

2013-10-01

There is a scarcity of outcome data regarding phase 1 trials for patients with gynecologic malignancy. The objective of this study was to assess toxicity, clinical benefit and prognosticators in gynecologic oncology patients participating in phase 1 trials. All phase 1 oncology trials conducted at Albert Einstein Cancer Center from 1999 to 2010 were reviewed and extracted for relevant demographic and clinical data concerning patients with gynecologic malignancy. Cox-proportional and logistic regression modeling were used for multivariate analysis. 120 distinct patients with gynecologic malignancy participated in 41 trials, constituting 30.6% of all phase 1 patients enrolled in the same time period. The median age is 59 years. Out of the 184 patients enrolled, 160 individual responses were evaluable. Seventeen DLT events (9.2%) occurred, including 1 (0.5%) treatment-related mortality. There were 27.2%≥ grade 3 hematologic and 24.4% non-hematologic toxicity. Eighty patients had stable disease (SD, 50%), including 21.9% with SD ≥ 4 months, 11 (6.3%) with partial response (PR), and 3 (1.9%) achieving complete response (CR). The clinical benefit rate (CBR=SD+CR+PR) was 58.1%. Albumin (Alb)≤ 3.5 g/dL and abnormal ANC were independent negative prognosticators of survival. We also found a continuous correlation between changes in Albumin (p=0.02) and LDH (p=0.02) and odds of achieving CBR≥4month. Our clinical outcome and safety data suggested that phase 1 trials may be a reasonable option for patients with advanced and recurrent gynecologic cancer. The potential prognosticators identified should be further validated in larger trials. © 2013.

Typhoid fever with severe abdominal pain: diagnosis and clinical findings using abdomen ultrasonogram, hematology-cell analysis and the Widal test.

PubMed

Arjunan, Maripandi; Al-Salamah, Ali A

2010-10-04

A six-year-old boy with high-grade fever and abdominal pain in the epigastric region was examined with ultrasonogram of the abdomen. Hematology-cell analysis, serology (Widal test), urine analysis, and blood cultures were also performed. The ultrasonogram was helpful for the identification of multiple organ involvement with Salmonella typhi. The results revealed mild hepatosplenomegaly, minimal ascitis, and mesenteric lympoadenopathy. Hematological analysis showed a white blood count of 6,300 cells mL-1; a red blood cell count of 4.54 million/cu mm. The erythrocyte sedimentation rate (ESR) was 24 mm/1 hr; hemoglobin level of 11.5 g/dl; and a platelet count of 206,000 cells/mL. The patient's serum was agglutinated with lipopolysaccharide (TO), the titre value was 1:320 dilution, and flagellar antigen (TH) titre was 1:640. The patient was diagnosed with typhoid fever. Ceftriaxone was given intravenously for five days and the patient fully recovered.

Biological therapy of hematologic malignancies: toward a chemotherapy-free era.

PubMed

Klener, Pavel; Etrych, Tomas; Klener, Pavel

2017-10-06

Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs. Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but also might fundamental change treatment paradigms of certain types of hematologic malignancies in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC).

PubMed

Reinmuth, N; Meyer, A; Hartwigsen, D; Schaeper, C; Huebner, G; Skock-Lober, R; Bier, A; Gerecke, U; Held, C-P; Reck, M

2014-03-01

Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population. 66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60 mg/m(2), subsequent cycles: 80 mg/m(2) in the absence of any hematological toxicity ≥ grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80 mg/m(2) i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin. Median age was 62.5 (33-82) years. In the overall population (n=66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n=58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥ 3 were moderate with no significant differences between the two treatment arms. Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The flavonolignan-silymarin protects enzymatic, hematological, and immune system against γ-radiation-induced toxicity.

PubMed

Adhikari, Manish; Arora, Rajesh

2016-06-01

The main focus of this study is evaluation of radioprotective efficacy of silymarin, a flavonolignan, against γ-radiation-induced damage to hematological, vital organs (liver and intestine), and immune system. Survival studies revealed that silymarin (administered orally for 3 days) provided maximum protection (67%) at 70 mg/kg body weight (b.wt.) against lethal 9 Gy γ-irradiation (dose reduction factor = 1.27). The study revealed significant (p < 0.05) changes in levels of catalase (12.57 ± 2.58 to 30.24 ± 4.89 units), glutathione peroxidase (6.23 ± 2.95 to 13.26 ± 1.36 µg of reduced glutathione consumed/min/mg protein), glutathione reductase (0.25 ± 5.6 to 11.65 ± 2.83 pM NADPH consumed/min/mg protein), and superoxide dismutase (11.74 ± 0.2 to 16.09 ± 3.47 SOD U/mg of protein) activity at 30th day. Silymarin pretreated irradiated group exhibited increased proliferation in erythrocyte count (1.76 ± 0.41 × 10(6) to 9.25 ± 0.24 × 10(6) ), hemoglobin (2.15 ± 0.48g/dL to 14.77 ± 0.25g/dL), hematocrit (4.55 ± 0.24% to 37.22 ± 0.21%), and total leucocyte count (1.4 ± 0.15 × 10(6) to 8.31 ± 0.47 × 10(6) ) as compared with radiation control group on 15th day. An increase in CD4:CD8 ratio was witnessed (0.2-1%) at 30th day time interval using flow cytometry. Silymarin also countered radiation-induced decrease (p < 0.05) in regulatory T-cells (Tregs ) (11.23% in radiation group at 7th day versus 0.1% in pretreated silymarin irradiated group at 15th day). The results of this study indicate that flavonolignan-silymarin protects enzymatic, hematological, and immune system against γ-radiation-induced toxicity and might prove useful in management of nuclear and radiological emergencies. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 641-654, 2016. © 2014 Wiley Periodicals, Inc.